WO2013082427A1 - Microneedle device including a peptide therapeutic agent and an amino acid and methods of making and using the same - Google Patents

Microneedle device including a peptide therapeutic agent and an amino acid and methods of making and using the same Download PDF

Info

Publication number
WO2013082427A1
WO2013082427A1 PCT/US2012/067292 US2012067292W WO2013082427A1 WO 2013082427 A1 WO2013082427 A1 WO 2013082427A1 US 2012067292 W US2012067292 W US 2012067292W WO 2013082427 A1 WO2013082427 A1 WO 2013082427A1
Authority
WO
Grant status
Application
Patent type
Prior art keywords
therapeutic agent
microneedles
peptide therapeutic
coating
amino acid
Prior art date
Application number
PCT/US2012/067292
Other languages
French (fr)
Inventor
Ying Zhang
Percy T. Fenn
Peter R. Johnson
Original Assignee
3M Innovative Properties Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0019Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0021Intradermal administration, e.g. through microneedle arrays, needleless injectors
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic, hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • A61K31/195Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • A61K31/198Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/41641,3-Diazoles
    • A61K31/4172Imidazole-alkanecarboxylic acids, e.g. histidine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22Hormones
    • A61K38/225Calcitonin gene related peptide
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22Hormones
    • A61K38/23Calcitonins
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22Hormones
    • A61K38/28Insulins
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22Hormones
    • A61K38/29Parathyroid hormone (parathormone); Parathyroid hormone-related peptides
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46Hydrolases (3)
    • A61K38/47Hydrolases (3) acting on glycosyl compounds (3.2), e.g. cellulases, lactases
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183Amino acids, e.g. glycine, EDTA or aspartame
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0087Galenical forms not covered by A61K9/02 - A61K9/7023
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L31/00Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08Materials for coatings
    • A61L31/10Macromolecular materials
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L31/00Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16Biologically active materials, e.g. therapeutic substances
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12YENZYMES
    • C12Y302/00Hydrolases acting on glycosyl compounds, i.e. glycosylases (3.2)
    • C12Y302/01Glycosidases, i.e. enzymes hydrolysing O- and S-glycosyl compounds (3.2.1)
    • C12Y302/01007Inulinase (3.2.1.7)
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/21Acids
    • A61L2300/214Amino acids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/252Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0023Drug applicators using microneedles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0046Solid microneedles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0053Methods for producing microneedles

Abstract

A medical device including an array of microneedles and a coating disposed on or within the microneedles and a method of making such a device are disclosed. The coating includes a peptide therapeutic agent and an amino acid. A method of stabilizing a peptide therapeutic agent with an amino acid on an array of microneedles is also disclosed. In some cases, the peptide therapeutic agent and the amino acid either both have a net positive charge or both have a net negative charge. In some cases, the peptide therapeutic agent is histidine.

Description

MICRONEEDLE DEVICE INCLUDING A PEPTIDE THERAPEUTIC AGENT AND AN AMINO ACID AND METHODS OF MAKING AND USING THE SAME

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority to U.S. Application Nos. 61/565,247 and 61/565,227, both filed

November 30, 2011, the disclosures of which are incorporated by reference in their entirety herein.

BACKGROUND

Transdermal delivery of a therapeutic agent such as a drug through the skin to the local tissue or systemic circulatory system without piercing the skin, such as with a transdermal patch, has been used successfully with a limited number of therapeutic molecules. The main barrier to transport of molecules through the skin is the stratum corneum (the outermost layer of the skin).

Devices including arrays of relatively small structures, sometimes referred to as microneedles or micro-pins, have been disclosed for use in connection with the delivery of therapeutic agents and other substances through the skin and other surfaces. The devices are typically pressed against the skin in an effort to pierce the stratum corneum such that the therapeutic agents and other substances can pass through that layer and into the tissues below.

Microneedle devices having a fluid reservoir and conduits through which a therapeutic substance may be delivered to the skin have been proposed, but there remain a number of difficulties with such systems, such as expense and the ability to make very fine channels that can reliably be used for fluid flow.

Microneedle devices having a dried coating on the surface of a microneedle array have also been developed. The devices are generally simpler than microneedle devices having fluid reservoirs and may directly introduce a therapeutic substance into the skin without the need for providing reliable control of fluid flow through very fine channels in the microneedle device.

SUMMARY

A challenging task in the development of peptide therapeutic agents, particularly polypeptides and proteins, is addressing physical (e.g., adsorption, aggregation, denaturation, or precipitation) and chemical (e.g, hydrolysis, oxidation, acylation, or deamidation) instability, which may cause loss of biological activity. It has now been found that the addition of an amino acid typically enhances the stability of a peptide therapeutic agent coated on a transdermal delivery device having an array of skin- piercing microneedles.

In one aspect, the present disclosure provides a medical device including an array of

microneedles a coating on or within at least a portion of the microneedles. The coating includes a peptide therapeutic agent and an amino acid, wherein the peptide therapeutic agent and the amino acid either both have a net positive charge or both have a net negative charge. The coating can be substantially free of sorbitol.

In another aspect, a method of making such a medical device is disclosed. The method typically includes:

providing an aqueous composition comprising a peptide therapeutic agent, an amino acid, and a buffer, wherein the peptide therapeutic agent and the amino acid either both have a net positive charge or both have a net negative charge in the aqueous composition;

contacting the microneedles with the composition; and

volatilizing a portion of the aqueous composition to provide a coating on a least a portion of the microneedles, wherein the coating comprises at least the peptide therapeutic agent and the amino acid.

In another aspect, the present disclosure provides a medical device including an array of microneedles a coating on or within at least a portion of the microneedles. The coating includes a peptide therapeutic agent and histidine. The molar ratio of the histidine to the peptide therapeutic agent can be less than 2: 1.

In another aspect, a method of making such a medical device is disclosed. The method typically includes:

providing an aqueous composition comprising a peptide therapeutic agent, histidine, and a buffer, wherein the molar ratio of the histidine to the peptide therapeutic agent is less than 2:1;

contacting the microneedles with the composition; and

volatilizing a portion of the aqueous composition to provide a coating on a least a portion of the microneedles, wherein the coating comprises at least the peptide therapeutic agent and the histidine.

In another aspect, the present disclosure provides a method of stabilizing a peptide therapeutic agent on or within an array of microneedles, the method comprising incorporating an amino acid into the array of microneedles. In some embodiments, the peptide therapeutic agent and the amino acid either both have a net positive charge or both have a net negative charge. In some embodiments, the amino acid is histidine. In some embodiments, the molar ratio of the amino acid (e.g., histidine) to the peptide therapeutic agent is less than 2:1.

In this application, terms such as "a", "an" and "the" are not intended to refer to only a singular entity, but include the general class of which a specific example may be used for illustration. The terms "a", "an", and "the" are used interchangeably with the term "at least one". The phrases "at least one of and "comprises at least one of" followed by a list refers to any one of the items in the list and any combination of two or more items in the list. All numerical ranges are inclusive of their endpoints and non-integral values between the endpoints unless otherwise stated.

As used in this specification and the appended claims, the term "or" is generally employed in its sense including "and/or" unless the content clearly dictates otherwise. For example, "a coating on or within at least a portion of the microneedles" means the coating is on and/or within at least a portion of the microneedles. Unless otherwise indicated, all numbers expressing feature sizes, amounts, and physical properties used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the foregoing specification and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by those skilled in the art utilizing the teachings disclosed herein.

The term "peptide" as used herein refers to peptides, polypeptides, and proteins. The terms "peptide", "polypeptide", and "protein" are interchangeable in the context of the present disclosure. These terms refer to a molecule having at least two amino acids linked through peptide bonds. The terms include oligopeptides, protein fragments, analogs, derivatives (e.g., glycosylated derivatives and pegylated derivatives), and fusion proteins.

All scientific and technical terms used herein have meanings commonly used in the art unless otherwise specified. The definitions provided herein are to facilitate understanding of certain terms used frequently herein and are not meant to limit the scope of the present disclosure.

In embodiments where weight percent is based upon total weight of solids, solids are those ingredients which are not volatile. For example, the total weight of solids does not include a volatilizable carrier (e.g., water or a volatile co-solvent).

The above summary of the present invention is not intended to describe each disclosed embodiment or every implementation of the present invention. The description that follows more particularly exemplifies illustrative embodiments. In the application, guidance is provided through lists of examples, which examples can be used in various combinations. In each instance, the recited list serves only as a representative group and should not be interpreted as an exclusive list.

BRIEF DESCRIPTION OF THE DRAWINGS

The disclosure may be more completely understood in consideration of the following detailed description of various embodiments of the disclosure in connection with the accompanying drawings, in which:

FIG. 1 is a schematic cross-sectional view of an uncoated microneedle array;

FIG. 2 is a schematic perspective view of a microneedle device in the form of a patch;

FIG. 3 is a schematic cross-sectional view of a coated microneedle array; and

FIG. 4 is an optical micrograph of coated microneedles in a microneedle array.

The figures are not necessarily to scale. Like numbers used in the figures refer to like components. However, it will be understood that the use of a number to refer to a component in a given figure is not intended to limit the component in another figure labeled with the same number. DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

In the following description, reference is made to the accompanying drawings that form a part hereof, and in which are shown by way of illustration several specific embodiments. It is to be understood that other embodiments are contemplated and may be made without departing from the scope or spirit of the present disclosure. The following detailed description, therefore, is not to be taken in a limiting sense.

With the development of recombinant DNA technology, a number of peptide therapeutic agents have become available for therapeutic use. These agents include octreotide, leuprolide, parathyroid hormone, luteinizing hormone releasing hormone, insulin, vascular endothelial growth factor, and many others. One challenging task in the development of peptide therapeutic agents is addressing physical (e.g., adsorption, aggregation, denaturation, or precipitation) and chemical (e.g., hydrolysis, oxidation, acylation, or deamidation) instability, which may cause loss of biological activity.

Oxidation is a major chemical degradation pathway of peptide therapeutic agents. The side chains of His, Met, Cys, Trp and Tyr residues in proteins are potential sites for oxidation. Some proteins are very sensitive to light during manufacturing and storage, which can also result in modification of the molecules. Both oxygen content and light exposure may cause oxidation and affect oxidation rate and promote aggregation or other degradation pathways. Oxidation can alter a protein's physiochemical characteristics and led to aggregation or fragmentation, which can negatively impact potency and immunogenicity. Acylation is another pathway of instability of peptide therapeutic agents. Nucleophilic primary amines, such as at the N-terminus or a lysine side chain, can react with carboxylate groups to form acylated peptide adducts. Peptide acylation may cause loss of activity, a change of receptor specificity, or immunogenicity. Protein aggregation is an example of physical instability, and aggregate formation can lead to loss of biological activity, loss of solubility, and increased immunogenicity.

These and other degradation pathways can result in loss of activity. It is therefore desirable to provide compositions for formulating and delivering peptide therapeutic agents having enhanced chemical and physical stability and exhibiting maximal shelf lives. It has now been found that amino acids are useful for stabilizing peptide therapeutic agents coated on and/or within a medical device having a plurality of skin-piercing microneedles. Without wishing to be bound by theory, it is believed that the addition of the amino acid substantially reduces the oxidation, photo-oxidation, acylation, and aggregation of peptide formulations.

A number of peptide therapeutic agents may usefully be incorporated into the medical devices according to and/or made according to the present disclosure. Exemplary peptide therapeutic agents include parathryroid hormone, calcitonin, lysozyme, insulin, glatiramer acetate, goserelin acetate, somatostatin , octreotide, leuprolide, vasopressin, thymosin alpha- 1, atrial natriuretic peptide (ANP), endorphin, growth factors (e.g., vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), erythropoietin(EPO), bone morphogenetic proteins (BMPs), and epidermal growth factor(EFG), granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony stimulating factor (GM- CSF), insulin-like growth factor (IGF), platelet-derived growth factor releasing factor), growth hormone release hormone (GHRH), interferons (e.g., interferon alpha, interferon beta, and interferon gamma), antimicrobial peptides, dornase alfa, tissue plasminogen activator, urokinase, ANP clearance inhibitors, luteinizing hormone releasing hormone (LHRH), Melanocyte Stimulating Hormones (alpha & Beta MSH), pituitary hormones (hGH), Adrenocorticotropic hormone (ACTH), , human chorionic

gonadotropin, streptokinase , interleukins, menotropins (urofollitropin (FSH) and LH)), protein C, protein S, , angiotensin, angiogenin, Endothelins, pentigetide, Brain natriuretic peptide (BNP), neuropeptide YJslet Amyloid Polypeptide (IAPP), Vasoactive intestinal peptide (VIP), hirudin, glucagon, insulin, insulinotropin analogs and derivatives of any of the foregoing peptide therapeutic agents, fusion proteins, and peptide vaccines. Peptide vaccines include those with an antigen in the form of a peptide as defined above. Exemplary peptide vaccines include therapeutic cancer vaccine, anthrax vaccine, flu vaccine, Lyme disease vaccine, rabies vaccine, measles vaccine, mumps vaccine, chicken pox vaccine, small pox vaccine, hepatitis vaccine, hepatitis A vaccine, hepatitis B vaccine, hepatitis C vaccine, pertussis vaccine, rubella vaccine, diphtheria vaccine, encephalitis vaccine, Japanese encephalitis vaccine, respiratory syncytial virus vaccine, yellow fever vaccine, polio vaccine, herpes vaccine, human papilloma virus vaccine, rotavirus vaccine, pneumococcal vaccine, meningitis vaccine, whooping cough vaccine, tetanus vaccine, typhoid fever vaccine, cholera vaccine, tuberculosis vaccine, severe acute respiratory syndrome (SARS) vaccine, HSV-1 vaccine, HSV-2 vaccine, HIV vaccine and combinations thereof. In some embodiments, the peptide vaccine includes at least one of influenza vaccine, polio vaccine, hepatitis A vaccine, and cancer vaccine.

In some embodiments, the peptide therapeutic agent is a parathyroid hormone-related protein. In some embodiments, the peptide therapeutic agent is a parathyroid hormone -related protein (PTHrP) analogue represented by formula [Glu22'25,Leu23'28'31,Aib29,Lys26'30]hPTHrP(l-34)NH2. This peptide therapeutic agent is useful for treating osteoporosis and is described in Int. Pat. Appl. Pub. No. WO 2008/063279 (Dey et al.). In these embodiments, the medical device need not be free of sorbitol.

Furthermore, in these embodiments, the molar ratio of the histidine to the peptide therapeutic agent need not be limited. For example, the molar ratio of the histidine to the peptide therapeutic agent need not be less than 2: 1 and may be more than 2: 1.

A number of amino acids may usefully be incorporated into the medical devices according to and/or made according to the present disclosure. Useful amino acids include naturally occurring amino acids and synthetic amino acids that are capable of having a net positive charge or a net negative charge. Typically, useful amino acids are capable of having a net positive charge or a net negative charge in a pH range from 3 to 11. The amino acids may have either L- or D- Fischer configuration. In some embodiments, the amino acid is histidine, arginine, lysine, aspartic acid, or glutamic acid. In some embodiments, the amino acid is histidine, lysine, or arginine. Such amino acids can be useful, in some embodiments, with peptide therapeutic agents having a net positive charge. In some embodiments, the amino acid is aspartic acid or glutamic acid. Such amino acids can be useful, in some embodiments, with peptide therapeutic agents having a net negative charge. In some embodiments, the amino acid is histidine. In the coatings disclosed herein or in a coating formulation, which may be an aqueous composition, the amino acid may be in salt form. In many embodiments, the peptide therapeutic agent and the amino acid either both have a net positive charge or both have a net negative charge. In some embodiments, the peptide therapeutic agent and the amino acid each have a net positive charge. For example, the peptide therapeutic agent may be parathyroid hormone, lysozyme, or salmon calcitonin, and the amino acid may be histidine, arginine, or lysine. In other embodiments, the peptide therapeutic agent and the amino acid each have a net negative charge. For example, the peptide therapeutic agent may be insulin, and the amino acid may be aspartic acid or glutamic acid. In embodiments where the peptide therapeutic agent and the amino acid each have a net positive charge and in embodiments where the peptide therapeutic agent and the amino acid each have a net negative charge, it may be said that the peptide therapeutic agent and the amino acid have the same charge or matched charges. That is, the charge on the peptide therapeutic agent and the amino acid might be considered the same or matched if the charge is in the same direction, regardless of the magnitude of the charge. An amino acid that has a net negative charge or a net positive charge may not be said to be a zwitterion (that is, neutral).

The net charges of the peptide therapeutic agent and the amino acid are typically established in a formulation that is used to coat the array of microneedles in the methods described hereinbelow.

Typically, the peptide therapeutic agent and the amino acid are dissolved or dispersed in a solvent at an established pH. For example, the pH may be in a range from 3 to 11, 4 to 10, 6 to 8, or 5.5 to 8.5. In some embodiments wherein the amino acid is histidine, the pH may be in a range from 3 to 6, 3 to 5, or 4 to 5. The formulation can be an aqueous composition that is buffered at a particular formulation pH. When a portion of the aqueous composition is volatized after coating the array of microneedles with the composition, the peptide therapeutic agent and the amino acid maintain their net charges and are incorporated into the coating.

Amino acids having a net charge may be said to be substantially in charged form since there is usually equilibrium between charged and neutral species. In some embodiments, the ratio of the charged form of the amino acid to the neutral form that may be present can be at least 10: 1. In some

embodiments, the ratio of the charged form of the amino acid to the neutral form is at least 100: 1, at least 1000: 1, or at least 10,000: 1. Such ratios can be determined in solution, for example, using the difference between the formulation pH and the pKa of the amino acid side chain. Amino acids useful for practicing the present disclosure are considered to have a net positive charge if their isoelectric points are higher than the formulation pH. Amino acids useful for practicing the present disclosure are considered to have a net negative charge if their isoelectric points are lower than the formulation pH.

For peptide therapeutic agents, when the isoelectric point is lower than the pH of the formulation, it typically is described as having a net negative charge. When the isoelectric point of the peptide therapeutic agent is higher than the pH of the formulation, it typically is described as having a net positive charge.

In some embodiments, it may be useful to define the net charges of the amino acid and the peptide therapeutic agent at physiological pH (e.g., in a range from 7 to 7.4). In these embodiments, if an isoelectric point of a peptide therapeutic agent is less than about 7, it typically is described as having a net negative charge. If an isoelectric point of a peptide therapeutic agent is greater than about 7, it typically is described as having a net positive charge.

In contrast to U. S. Pat. App. Pub. No. 2006/0188555 (Cormier et al.), which suggests that therapeutic peptide agents should be formulated with particular counterions to limit fibril formation in a formulation, it has now been found that formulations and coatings including peptide therapeutic agent and amino acids that do not have opposite net charges have useful physical and chemical stability. In embodiments where the peptide therapeutic agent and the amino acid either both have a net positive charge or both have a net negative charge, the amino acids cannot be considered to be counterions for the peptide therapeutic agents.

In some embodiments, the amino acid is histidine. Histidine may be useful in coatings containing a peptide therapeutic agent with either a net positive charge or a net negative charge. In coatings disclosed herein, histidine may stabilize a wide variety of peptide therapeutic agents (e.g., both net negatively charged and net positively charged) to at 40 °C and 96% relative humidity to a greater extent that several other amino acids.

In the medical device according to and/or made according to the present disclosure, the amino acid may be present in a variety of useful amounts relative to the peptide therapeutic agent. In some embodiments, including any one of the above embodiments, the molar ratio of the amino acid to the peptide therapeutic agent is in a range from 0.25: 1 to 51 : 1. In some embodiments, the molar ratio of the amino acid to the peptide therapeutic agent is in a range from 0.5: 1 to 25: 1 or 0.5:1 to 20: 1.

Advantageously, in many embodiments, a large excess of the amino acid is not required. In these embodiments, the molar ratio of the amino acid to the peptide therapeutic agent may be less than 2: 1, less than 1.5: 1, or less than 1: 1. For example, the molar ratio of the amino acid to the peptide therapeutic agent may be in a range from 0.5: 1 to 2: 1, 0.5: 1 to 1.5: 1, or 0.5: 1 to 1 : 1. In embodiments where molar ratio of the amino acid to the peptide therapeutic agent may be less than 2: 1, less than 1.5: 1, or less than 1 : 1, the amino acids would generally not be considered to be present in a sufficient amount to neutralize the peptide therapeutic agents.

In some embodiments, including any one of the above embodiments, particularly when the coating is on an external surface of the microneedles or on an interior surface of hollow microneedles, the amino acid is present in an amount of at least 0.1 weight percent based upon total weight of solids in the coating, in some embodiments at least 0.5 weight percent, in some embodiments at least 1 weight percent, and in some embodiments at least 2 weight percent. In some embodiments, the amino acid is present in an amount of up to 25 weight percent, in some embodiments, up to 15 weight percent, in some embodiments up to 10, 9, or 8 weight percent, based upon the total weight of solids in the coating. In some embodiments, the amino acid is present in an amount of 0.1 weight percent to 20 weight percent,

0.1 weight percent to 10 weight percent, or 1 weight percent to 8 weight percent, based upon total weight of solids in the coating. In some embodiments, including any one of the above embodiments, particularly when the coating is on an external surface of the microneedles or on an interior surface of hollow microneedles, the peptide therapeutic agent is present in an amount of at least 10 weight percent based upon total weight of solids in the coating, in some embodiments at least 20 weight percent, in some embodiments at least 50 weight percent, and in some embodiments at least 60 weight percent. In some embodiments, the peptide therapeutic agent is present in an amount of up to 99.9 weight percent, in some embodiments, up to 99.5 weight percent, in some embodiments up to 99, 95, or 92 weight percent, based on the total weight of solids in the coating. In some embodiments, the peptide therapeutic agent is present in an amount of 10 weight percent to 99.9 weight percent, 50 weight percent to 99.5 weight percent, or 50 weight percent to 95 weight percent, based upon total weight of solids in the coating.

The coatings disclosed herein may also contain at least one excipient. An excipient can function to maintain the active nature of the peptide therapeutic agent, to facilitate the performance of a coating formulation when depositing a coating on the microneedles, to resist disruption of the coating or the microneedle structure itself when penetrating the stratum corneum or other tissue, or a combination thereof. Exemplary excipients include, for example, buffers, carbohydrates, polymers, surfactants, nonvolatile non-aqueous solvents, acids, bases, antioxidants, saccharin (e.g., saccharin sodium dehydrate), lipids (e.g., dipalmitoylphosphatidylcholine (DPPC)), and inorganic salts (e.g., sodium chloride and potassium chloride).

The amount of the at least one excipient in the coating and therefore in the coating formulation used for depositing the coating can vary depending on at least one of the identity of the components in the coating formulation, the amount of peptide therapeutic agent and amino acid desired on the microneedle array, the type of microneedle array being coated, the shape and location of the coating on the microneedle, or other considerations.

In some embodiments, the method of making a medical device including microneedles according to the present disclosure includes providing an aqueous composition comprising a peptide therapeutic agent, an amino acid, and a buffer. Similarly, aqueous compositions disclosed herein useful for coating an array of microneedles typically include the peptide therapeutic agent, the amino acid, and a buffer. A buffer generally functions to stabilize the pH of a coating formulation used for depositing the coating on the microneedles. The particular buffer to be utilized can depend at least in part on the particular peptide therapeutic agent and amino acid that are included in the coating. The pH of the formulation can, for example, help to maintain the solubility of the peptide therapeutic agent and amino acid in the composition. As described above, the pH also generally controls the charges on the amino acid and the peptide therapeutic agent.

A variety of buffers can be useful in the aqueous compositions useful for practicing the present disclosure. Exemplary buffers include histidine, phosphate buffers, acetate buffers, citrate buffers, glycine buffers, ammonium acetate buffers, succinate buffers, pyrophosphate buffers, Tris acetate (TA) buffers, and Tris buffers. Buffered saline solutions can also be utilized as buffers. Exemplary buffered saline solutions include phosphate buffered saline (PBS), Tris buffered saline (TBS), saline-sodium acetate buffer (SSA), and saline-sodium citrate buffer (SSC). In some embodiments, phosphate buffered saline is used for the aqueous composition. A wide variety of pH values may be useful depending, for example, on the peptide therapeutic agent and the amino acid. In some embodiments, the pH may be in a range from 3 to 11, 4 to 10, 6 to 8, or 5.5 to 8.5. In some embodiments, for example, wherein the amino acid is histidine, the pH may be in a range from 3 to 6, 3 to 5, or 4 to 5.

It should be understood that in aqueous compositions disclosed herein that include a peptide therapeutic agent, an amino acid, and a buffer, a single amino acid cannot serve as both the amino acid component and the buffer. For example, in aqueous compositions including a peptide therapeutic agent, an amino acid, and a buffer in which histidine is used as a buffer, another amino acid is present as the amino acid component. Furthermore, it should be understood that the amino acid in the aqueous compositions useful for practicing the present disclosure does not necessarily buffer the aqueous composition.

In some embodiments, the coating comprising the peptide therapeutic agent and the amino acid or the aqueous composition disclosed herein further comprises a carbohydrate. The carbohydrate may be useful, for example, for stabilizing the aqueous composition containing a peptide therapeutic agent useful for coating the microneedles in the method disclosed herein. The carbohydrate can be a saccharide, including mono-, di-, and polysaccharides, and may include, for example, non-reducing sugars such as raffinose, stachyose, sucrose, and trehalose; and reducing sugars such as monosaccharides and disaccharides. Exemplary monosacharides include apiose, arabinose, digitoxose, fucose, fructose, galactose, glucose, gulose, hamamelose, idose, lyxose, mannose, ribose, tagatose, sorbitol, xylitol, and xylose. Exemplary disaccharides include sucrose, trehalose, cellobiose, gentiobiose, lactose, lactulose, maltose, melibiose, primeverose, rutinose, scillabiose, sophorose, turanose, and vicianose. In

embodiments, sucrose, trehalose, fructose, maltose, or combinations thereof can be utilized. All optical isomers of exemplified sugars (D, L, and racemic mixtures) are also included herein. Useful

polysaccharides include starches such as hydroxyethyl starch, pregelatinized corn starch, pentastarch, dextrin, dextran or dextran sulfate, gamma-cyclodextrin, alpha-clyclodextrin, beta-clyclodextrin, glucosyl-alpha-cylcodextrin, maltosyl-alpha-cyclodextrin, glucosyl-beta-cyclodextrin, maltosyl-beta- cyclodextrin, 2-hydroxy-beta-cyclodextrin, 2-hydroxypropyl-beta-cyclodextrin, 2-hydroxypropyl-gamma- cyclodextrin, hydroxyethyl-beta-cyclodextrin, methyl-beta-cyclodextrin, sulfobutylether-alpha- cyclodextrin, sulfobutylether-beta-cyclodextrin, and sulfobutylether-gamma-cyclodextrin. In

embodiments, hydroxyethyl starch, dextrin, dextran, gamma-clyclodextrin, beta-cyclodextrin, or combinations thereof can be utilized. In embodiments, dextrans having an average molecular mass of 35,000 to 76,000 can be utilized. In some embodiments, the at least one carbohydrate is a cellulose. Suitable celluloses include hydroxyethyl cellulose (HEC), methyl cellulose (MC), microcrystalline cellulose, hydroxypropyl methyl cellulose (HPMC), hydroxy ethylmethyl cellulose (HEMC),

hydroxypropyl cellulose (HPC), and mixtures thereof. Advantageously, typically, the aqueous composition and the coating comprising the peptide therapeutic agent and the amino acid are stable even in the absence of a carbohydrate. In some of these embodiments, the aqueous composition and the coating are substantially free of a carbohydrate. For example, the aqueous composition and the coating can be substantially free of a saccharides, including mono-, di-, and polysaccharides. For example, the aqueous composition and the coating may be free of any of the mono-, di-, and polysaccharides listed above. In some embodiments of the medical device according to the present disclosure is substantially free of sorbitol. In some embodiments of the method according the present disclosure, the aqueous composition is substantially free of sorbitol. "Substantially free", referring to any carbohydrate listed above or sorbitol, means that a carbohydrate or sorbitol could be present but in an amount less than necessary to stabilize the aqueous composition or the coating.

"Substantially free" of a specific carbohydrate or sorbitol includes being free of the carbohydrate or sorbitol and further includes wherein the molar amount of the carbohydrate or sorbitol is less than the molar amount of peptide therapeutic agent. In some embodiments, the term "substantially free" of a specific carbohydrate or sorbitol means that the amount of the carbohydrate or sorbitol is less than 4, 3, 2, or 1 percent by mole or by weight, based on the total amount of solids in the composition. In some embodiments, the aqueous composition and/or the coating comprising the peptide therapeutic agent and the amino acid are free of carbohydrates. In some embodiments, the aqueous composition and/or the coating comprising the peptide therapeutic agent and the amino acid are free of sorbitol.

In some embodiments, the aqueous composition and the coating disclosed herein include at least one surfactant. The at least one surfactant can be amphoteric, cationic, anionic, or nonionic. Exemplary suitable surfactants include lecithin, polysorbates ( e.g., polysorbate 20, polysorbate 40, and polysorbate 80), glycerol, sodium lauroamphoacetate, sodium dodecyl sulfate, cetylpyridinium chloride (CPC), dodecyltrimethyl ammonium chloride (DoTAC), sodium desoxycholate, benzalkonium chloride, sorbitan laurate, and alkoxylated alcohols (e.g., laureth-4). Advantageously, in some embodiments, surfactants are not necessary in the coatings and the aqueous compositions disclosed herein. In some of these embodiments, the aqueous composition and the coating are substantially free of surfactant. "Substantially free of surfactant" refers to being free of surfactant or having up to 1, 0.5, 0.1, or 0.01 percent by weight surfactant, based on the total solids in the composition or coating.

Non- volatile, non-aqueous solvents may be useful in the aqueous compositions disclosed herein and may be present in the resulting coatings. Exemplary suitable non-volatile, non-aqueous solvents include propylene glycol, dimethylsulf oxide, glycerin, 1 -methyl -2 -pyrrolidinone, and N,N- dimethy If or mamide .

The aqueous compositions and the coatings disclosed herein may include at least one antioxidant. Exemplary suitable antioxidants include sodium citrate, citric acid, ascorbic acid, methionine, sodium ascorbate, and combinations thereof. Advantageously, in some embodiments, such antioxidants are not necessary in the coatings and the aqueous compositions disclosed herein. In some of these embodiments, the aqueous composition and the coating can have up to 1, 0.5, 0.1, or 0.01 percent by weight of any of these antioxidants, based on the total solids in the composition or coating.

In some embodiments, the coating or the aqueous composition disclosed herein includes at least one polymer. Exemplary useful polymers include polyvinyl pyrrolidone (PVP), polyethylene glycol (PEG), polyvinyl alcohol (PVA), and polyethylene glycol sorbitan isostearate. In some embodiments, PVPs having a number average molecular weight of 5,000 to 1.5 million may be useful. In some embodiments, polyethylene glycols having a number average molecular weight of 300 to 8,000 may be useful.

In some embodiments, the coating or the aqueous composition disclosed herein may include a polypeptide other than the peptide therapeutic agent. The amino acids making up the polypeptide may be the same or at least some may be different from each other. Exemplary useful polyamino acids (the same amino acids) can include polyhistidine, polyaspartic acid, and polylysine.

In some embodiments of the coatings and aqueous compositions, counterions for the peptide therapeutic agent and/or the amino acid are present. Exemplary weak acids useful for providing counterions for postively charged peptide therapeutic agents or amino acids include acetic acid, propionic acid, pentanoic acid, citric acid, succinic acid, glycolic acid, gluconic acid, glucuronic acid, lactic acid, malic acid, pyruvic acid, tartaric acid, tartronic acid, fumaric acid, malonic acid, butyric acid, crotonic acid, digylcolic acid, and glutaric acid. Exemplary strong acids useful for providing counterions for postively charged peptide therapeutic agents or amino acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfonic acid, sulfuric acid, maleic acid, phosphoric acid, benzene sulfonic acid, and methane sulfonic acid. Exemplary weak bases useful for providing counterions for negative charged peptide therapeutic agents or amino acids include ammonia, morpholine, monoethanolamine, diethanolamine, triethanolamine, tromethamine, methylglucamine, and glucosamine. Exemplary strong bases useful for providing counterions for negative charged peptide therapeutic agents or amino acids include sodium hydroxide, potassium hydroxide, calcium hydroxide, and magnesium hydroxide.

The method of making a medical device comprising microneedles according to the present disclosure includes providing an aqueous composition comprising a peptide therapeutic agent, an amino acid, and, in some embodiments, a buffer. Accordingly, the present disclosure also provides an aqueous composition suitable for coating an array of microneedles. The aqueous composition includes a peptide therapeutic agent, an amino acid, and optionally a buffer. The amounts of these ingredients in the composition are chosen in order to achieve the above described amounts of the solid, non-volatile ingredients in the resulting coating deposited on the microneedles. The aqueous composition may further include any of the excipients described above. The coating is deposited on the microneedles by contacting the microneedles with the composition.

In addition to water, which serves as a volatilizable carrier, the aqueous composition can also include at least one co-solvent (which may also be a volatilizable carrier). Exemplary useful co-solvents, which may be volatilizable carriers, include ethanol, isopropanol, methanol, propanol, and butanol. Ci_4 ethers, Ci_4 ketones, and Ci_4 esters, for example, may also be useful. Useful volatile co-solvents are typically those having a boiling point up to 120 °C, in some embodiments up to 100 °C. Non-volatile co- solvents may also be included as described above. Generally, the solvent in the coating formulation is selected such that it may dissolve or disperse the peptide therapeutic agent, the amino acid, and any excipients that may be present. The aqueous compositions can have an overall solids content from 5% to 80% by weight, from 10% to 70% by weight, or from 50% to 70% by weight, based on the total weight of the aqueous composition.

Aqueous compositions useful for depositing the coating on the microneedles can be designed to have a desired viscosity, surface tension, and/or contact angle of the aqueous composition on the material comprising the microneedles.

The viscosity of the aqueous composition can be an important factor for providing a desired amount of uniform coatings on the microneedles. The desired viscosity of the aqueous composition can depend at least in part on at least one of the geometry of the microneedles, the particular coating method being utilized, and the desired number of coating steps, among other factors. In some embodiments, the aqueous composition has a shear viscosity in a range from 500 to 30,000 centipoise (cps) (in some embodiments, in a range from 500 to 10,000 cps or 500 to 8,000 cps) when measured at a shear rate of 100s"1 at a temperature of 25° C. The shear viscosity is a measurement of the resistance of a fluid to being deformed by shear stress. Various instruments can be used for viscosity testing, including rheometers, for example rheometers from TA Instruments (New Castle, DE).

The surface tension of the aqueous composition can be an important factor for providing a desired amount of material on the microneedles without excessive spreading along the needle or onto the microneedle substrate. The desired surface tension of the aqueous composition can depend at least in part on at least one of the geometry of the microneedles, the particular coating method being utilized, and the desired number of coating steps, among other factors. In some embodiments, the aqueous composition has a surface tension (measured at ambient, or room temperature conditions) up to 60 dynes/cm, in some embodiments, up to 55 dynes/cm. In some embodiments, the aqueous composition has a surface tension in a range from 40 dynes/cm to 55 dynes/cm. The surface tension can be determined using the pendant drop method. In a pendant drop method of measuring surface tension, a drop of liquid is suspended from the end of a tube by surface tension. The force due to surface tension is proportional to the length of the boundary between the liquid and the tube. Various instruments that encompass optical systems for measuring the relevant parameters of the drop and software packages for calculating the surface tension based on the measured parameters can be utilized herein. An exemplary instrument includes the Drop Shape Analysis System (Model DSA 100S) available from Kriiss (Hamburg, Germany).

The contact angle of the aqueous composition on the material comprising the microneedles (also referred to as the "microneedle material") can be an important factor for providing a desired amount of material on the microneedles without excessive spreading along the needle or onto the microneedle substrate. The desired contact angle of the aqueous composition on the microneedle material can depend at least in part on at least one of the composition of the microneedles, the geometry of the microneedles, the particular coating method being utilized, and the desired number of coating steps, among other factors. In some embodiments, the aqueous composition has a contact angle (measured at ambient, or room temperature conditions) with the microneedle material of at least 50 degrees, at least 55 degrees, or at least 65 degrees. The contact angle of the aqueous composition on the microneedle material can be measured using various methods, for example, using the sessile drop method. Generally, a goniometer (or an instrument that employs a goniometer) can be utilized to measure contact angles; an example of such an instrument is the Drop Shape Analysis System (Model DSA 100S) available from Kriiss

(Hamburg, Germany). In embodiments, the contact angle can be measured within 5 seconds of the transfer of the aqueous composition onto the substrate (microneedle material). The contact angle of the aqueous composition with respect to the microneedle material is measured on a horizontal substrate made of the microneedle material.

The microneedle material can be (or include) silicon or a metal such as stainless steel, titanium, or nickel titanium alloy. The microneedle material can also be (or include) a medical grade polymeric material. In some embodiments, including any one of the above embodiments, the microneedle material can be a medical grade polymeric material. Exemplary types of medical grade polymeric materials include polycarbonate and liquid crystalline polymer (referred to herein as "LCP").

Generally, an "array" refers to medical devices described herein that include more than one (in embodiments, a plurality) structure capable of piercing the stratum corneum to facilitate the transdermal delivery of the peptide therapeutic agent and amino acid to the skin. The terms "microstructure" and "microneedle" refer to the structures associated with an array that are capable of piercing the stratum corneum to facilitate the transdermal delivery of the peptide therapeutic agent and amino acid to the skin. By way of example, microstructures can include needle or needle-like structures as well as other structures capable of piercing the stratum corneum. The term "microneedle array" or "array of microneedles" therefore can refer to a plurality of structures that are capable of piercing the stratum corneum to facilitate the transdermal delivery of the peptide therapeutic agent and amino acid to the skin.

Microneedle arrays useful for practicing the present disclosure can have a variety of

configurations, such as those described in the following patents and patent applications, the disclosures of which are incorporated herein by reference thereto. One embodiment for the microneedle arrays includes the structures disclosed in U. S. Patent Application Publication No. 2005/0261631 (Clarke et al.), which describes microneedles having a truncated tapered shape and a controlled aspect ratio. A further embodiment for the microneedle arrays includes the structures disclosed in U.S. Patent No. 6,881,203 (Delmore et al.), which describes tapered microneedles with at least one channel formed on the outside surface. Another embodiment for the microneedle arrays includes the structures disclosed in Int. App. Pub. Nos. WO2011/014514 (Gonzalez et al.) and WO2010/059065 (Burton et al.), which both describe hollow microneedles. For hollow microneedles, either the concave surface, the convex surface, or both may include the coating disclosed herein. A coating on the concave surface may be considered "within" the microneedles. In some embodiments, the microneedles are solid microneedles (that is, the microneedles are solid throughout).

Generally, a microneedle array includes a plurality of microneedles. FIG. 1 shows a portion of a microneedle array 100 that includes four microneedles 110 (of which two are referenced in FIG. 1) positioned on a microneedle substrate 120. Each microneedle 110 has a height h, which is the length from the tip of the microneedle 110 to the microneedle base at substrate 120. Either the height of a single microneedle or the average height of all microneedles on the microneedle array can be referred to as the height of the microneedle, h. In some embodiments, including any one of the embodiments described herein, each of the plurality of microneedles (or the average of all of the plurality of microneedles) has a height of about 100 to 1200 micrometers (μιη), in some embodiments about 200 to 1000 μιη, or about 200 to 750 μιη. In some embodiments, including any one of the embodiments described herein, the array of microneedles contains 200 to 1500 microneedles per cm2 of the array of microneedles.

A single microneedle or the plurality of microneedles in a microneedle array can also be characterized by their aspect ratio. The aspect ratio of a microneedle is the ratio of the height of the microneedle, h, to the width (at the base of the microneedle), w (as seen in FIG. 1). The aspect ratio can be presented as h:w. In some embodiments, including any one of the embodiments described herein, each of the plurality of microneedles (or the average of all of the plurality of microneedles) has (have) an aspect ratio in the range of 2: 1 to 5: 1. In some of these embodiments, each of the plurality of microneedles (or the average of all of the plurality of microneedles) has (have) an aspect ratio of at least 3: 1.

A microneedle or the plurality of microneedles in a microneedle array useful for practicing the present disclosure can have a variety of shapes. In some embodiments, including any one of the embodiments described herein, each of the plurality of microneedles can have a square pyramidal shape or the shape of a hypodermic needle. In some of these embodiments, the shape is square pyramidal.

In some embodiments, including any one of the embodiments described herein, the medical device according to the present disclosure may be in the form of a patch. One example of such an embodiment is shown in more detail in FIG. 2. FIG. 2 illustrates a medical device comprising a patch 20 in the form of a combination of a microneedle array 22, pressure sensitive adhesive 24 and backing 26. Such a patch 20 or another device including multiple microneedle arrays or multiple patches 20 can be referred to as a delivery device. The microneedle array 22 is illustrated with microneedles 10 protruding from a microneedle substrate 14. The microneedles 10 may be arranged in any desired pattern or distributed over the microneedle substrate 14 randomly. As shown, the microneedles 10 are arranged in uniformly spaced rows. In some embodiments, including any one of the embodiments described herein, microneedle arrays can have a surface area on the non-structured surface of more than about 0.1 cm2 and less than about 20 cm2. In some of these embodiments, the microneedle array area is at least about 0.5 cm2 and up to about 5 cm2. In one embodiment (not shown), a portion of the substrate 14 of the patch 20 is not provided with microneedles (that is, it is non-structured). In some of these embodiments, the non- structured surface has an area of more than about 1 percent and less than about 75 percent of the total area of the device surface that faces a skin surface of a patient. In another of these embodiments, the non- structured surface has an area of more than about 0.10 square inch (0.65 cm2) to less than about 1 square inch (6.5 cm2). In another embodiment (shown in FIG. 2), the microneedles are disposed over substantially the entire surface area of the array 22, such that there is essentially no non-structured area.

In the method of making a medical device described herein, contacting the microneedles with the aqueous composition can be carried out by dip coating the microneedles. Such methods are described, for example, U.S. Pat. App. Publ. No. 2008/0051699 (Choi et al.), the disclosure of which is incorporated herein by reference particularly with reference to FIGS. 10A, 10B, and IOC therein.

When dip coating, wasting peptide therapeutic agent and amino acid is avoided by contacting only a portion of the microneedle height with the aqueous composition and avoiding contact with the microneedle substrate. FIG. 3 illustrates, in cross-section, a portion of a microneedle array 200 that includes four microneedles 210 (of which two are referenced in FIG. 3) positioned on a microneedle substrate 220. Coating 250 is disposed on microneedles 210 at a distance 260 from the tip of the microneedles. This is accomplished by contacting not more than a portion of the microneedle height with the aqueous composition. Accordingly, in some embodiments, including any one of the method embodiments described herein that includes contacting the microneedles with the aqueous composition, the microneedles each have a tip and a base, the tip extending a distance (h) from the base, and contacting is carried out by contacting the tips of the microneedles and a portion of the microneedles extending not more than 90 percent of the distance (0.9h) from the tips to the bases with the composition, in some embodiments not more than 70 percent of the distance (0.7h), or not more than 50 percent of the distance (0.5h). It is to be understood that the distance can apply to a single microneedle or to an average of the microneedles in an array. In some embodiments, including any one of the embodiments described herein which includes a coating disposed on the microneedles, at least 50 % of the microneedles have the coating present on the microneedles near the tip and extending not more than 90 percent of the distance toward the base, preferably not more than 70 percent of the distance, more preferably not more than 50 percent of the distance.

In some embodiments, when the microneedles are contacted with the aqueous composition, the microneedles are facing downward into the aqueous composition. In some of these embodiments, after the microneedles are contacted with the aqueous composition, contacting is terminated and the microneedles are positioned facing upward before and/or during volatilizing a portion of the aqueous composition. In this position, a portion of the aqueous composition remaining on the microneedles may flow toward the base, leaving the tips of the microneedles exposed or with only as small amount of coating on the tips. The degree to which flow occurs can depend upon factors such as the viscosity, contact angle, and surface tension as described above.

After removing the microneedles from the aqueous composition, some of the coating formulation remains on the microneedles, the amount depending upon the aqueous composition properties and surface properties of the microneedle material as described above. At least a portion of the water is removed from the aqueous composition adhering to the microneedles, leaving the coating disposed on the microneedles. One or more additional contacting steps may be used. The shape of the coating, average coating thickness, and amount of the surface of the microneedle covered by the coating depends upon the factors discussed above as well as the number of times the contacting step is repeated.

FIG. 3 illustrates one embodiment with the coating disposed on the microneedles, wherein the tips of the microneedles are essentially exposed (no coating or a relatively small amount of coating) a distance 270 from the tip. In some embodiments, including any one of the embodiments described herein which includes a coating disposed on the microneedles, the tips of the microneedles are exposed or only as small amount of coating is on the tips. In some of these embodiments distance 270 is at least 1 percent (O. lh), 3 percent (0.03h) or 6 percent (0.06h) of the distance from the tip to the base. In some of these embodiments, distance 270 is at most 10 percent (O.lh) of the distance from the tip to the base.

In some embodiments, including any one of the embodiments described herein which includes a coating disposed on or within the microneedles, the coating is present on the microneedles in an average amount of 0.01 to 2 micrograms per microneedle. Coating weight can be determined by weighing the microneedle array before and after the coating is disposed on the microneedles and dividing the difference by the number of microneedles in the array. This measurement can be made once the coated microneedle array has come to a constant weight, indicating that the water and any other volatilizable carrier has been sufficiently removed, before taking the weight after coating. Alternatively, the total amount of a solid component in the coating on all the microneedles of the entire array can be determined analytically and then the total weight of solids calculated based upon the know weight of all solid components used in the aqueous composition.

Volatilizing the water and any other carrier can be performed using various means including for example, drying at ambient conditions; drying at conditions other than ambient conditions (such as temperatures other than room temperature or a humidity other than an average humidity); drying for various times; drying with heat, lyophilization, freeze drying; other similar techniques; or combinations thereof.

FIG. 4 is an optical micrograph illustrating three microneedles of a microneedle array after contacting the microneedles with the aqueous composition and removing a portion of the aqueous composition as described in Example 14.

Once a portion of the aqueous composition (which may be a portion or all of the water or nonaqueous solvent) in the aqueous composition has evaporated (either after a single contacting step or multiple contacting steps), the aqueous composition on the microneedle array can be referred to as the "coating" as described above. A coating as described herein can generally be referred to as a dried coating or a solid coating.

In some embodiments, a medical device according to the present disclosure can include an array of dissolvable microneedles. The dissolvable microneedles may contain the peptide therapeutic agent and the amino acid in the various amounts described above for coatings disposed on the microneedles.

Dissolvable microneedles further include a dissolvable matrix material. The dissolvable matrix material may be any solid material which dissolves sufficiently in the tissue underlying the stratum corneum to allow the peptide therapeutic agent and amino acid to be released into the tissue. In some embodiments, the dissolvable matrix material is selected from the group consisting of hyaluronic acid,

carboxymethylcellulose, hydroxpropylmethylcellulose, methylcellulose, polyvinyl alcohol, polyvinyl pyrrolidone, sucrose, glucose, dextran, trehalose, maltodextrin, and a combination thereof.

Dissolvable microneedle arrays may be fabricated by casting and drying a solution containing volatilizable carrier and dissolvable matrix material (preferably water soluble) in a mold containing the microstructured cavities. The internal shape of the microstructured cavities corresponds to the external shape of the dissolvable microneedles. The mold can be comprised of materials such as

polydimethylsiloxane (PDMS) or other plastics that do not permanently bind to or that have low adhesion to materials used to make the dissolvable microneedles.

The peptide therapeutic agent and amino acid component can be incorporated into dissolvable microneedles by first loading a solution of these components with a volatilizable carrier (preferably also including the dissolvable matrix material) into the mold containing microstructured cavities. After at least partially drying (volatilizing at least a portion of the volatilizable carrier), the mold is filled with a solution of dissolvable matrix material (without the peptide therapeutic agent and amino acid), followed by drying. Alternatively, in a one-step process, the peptide therapeutic agent and the amino acid can be combined with the dissolvable matrix material in a solution with the volatilizable carrier and the mold filled with this solution, followed by drying. The volatilizable carriers can include water or any of the volatile non-aqueous solvents (e.g., ethanol) described above. Drying can be carried out using any of the techniques described above.

In embodiments including dissolvable microneedles, the coating comprising the peptide therapeutic agent and the amino acid may be considered to be within a least a portion of the microneedles.

Application of the microneedle device may be carried out by contacting the tissue of a subject with the microneedles and applying hand pressure to force the microneedles into the tissue. Alternatively, an application device may be used which applies the pressure, forcing the microneedles into the tissue. This can provide a more even distribution of pressure and force the microneedles into the tissue at an optimum velocity so that essentially all of the microneedles can release the peptide therapeutic agent into the tissue. In some embodiments, contacting the tissue with a microneedle device is carried out at a microneedle velocity of 5 to 10 meters/second. The "subject" can include humans, sheep, horses, cattle, pigs, dogs, cats, rats, mice, or other mammals. Selected Embodiments of the Disclosure

1. A medical device comprising: an array of microneedles; and

a coating on or within at least a portion of the microneedles, wherein the coating comprises: a peptide therapeutic agent; and

an amino acid,

wherein the peptide therapeutic agent and the amino acid either both have a net positive charge or both have a net negative charge, and wherein the coating is substantially free of sorbitol.

2. The medical device of embodiment 1 , wherein the molar ratio of the amino acid to the peptide therapeutic agent is less than 2: 1.

3. The medical device of embodiment 1, wherein the molar ratio of the amino acid to the peptide therapeutic agent is in a range from 0.5: 1 to 55: 1.

4. The medical device of any one of embodiments 1 to 3, wherein the amino acid is histidine, arginine, lysine, aspartic acid, or glutamic acid.

5. The medical device of embodiment 4, wherein the amino acid is histidine.

6. The medical device of any one of embodiments 1 to 5, wherein the peptide therapeutic agent and the amino acid each have a net positive charge.

7. The medical device of any one of embodiments 1 to 4, wherein the peptide therapeutic agent and the amino acid each have a net negative charge.

8. The medical device of any one of embodiments 1 to 7, wherein the amino acid is present in the coating in a range from 0.1 to 15 percent by weight, based on the total weight of the coating.

9. The medical device of any one of embodiments 1 to 8, wherein the array of microneedles comprises a dissolvable matrix material.

10. The medical device of any one of embodiments 1 to 8, wherein at least some of the microneedles are hollow.

11. A medical device comprising:

an array of microneedles; and

a coating on or within at least a portion of the microneedles, wherein the coating comprises: a peptide therapeutic agent; and histidine,

wherein the molar ratio of the histidine to the peptide therapeutic agent is less than 2: 1.

12. The medical device of embodiment 11, wherein the molar ratio of the histidine to the peptide therapeutic agent is less than 1.5: 1.

13. The medical device of embodiment 11 or 12, wherein the peptide therapeutic agent has a net positive charge. 14. The medical device of embodiment 11 or 12, wherein the peptide therapeutic agent has a net negative charge.

15. The medical device of any one of embodiments 11 to 14, wherein histidine is present in the coating in a range from 0.1 to 15 percent by weight, based on the total weight of the coating.

16. The medical device of any one of embodiments 11 to 15, wherein the histidine stabilizes the peptide therapeutic agent in the coating.

17. The medical device of any preceding embodiment, wherein the peptide therapeutic agent is parathryroid hormone, calcitonin, lysozyme, insulin, glatiramer acetate, goserelin acetate, octreotide, leuprolide, vasopressin, atrial natriuretic peptide(ANP), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), erythropoietin(EPO), bone morphogenetic proteins(BMPs), epidermal growth factor(EFG), granulocyte clony-stimulating factor (G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF), interferon alpha, interferon beta, interferon gamma, antimicrobial peptides, dornase alfa, tissue plasminogen activator, a fusion protein, or a vaccine.

18. The medical device of any one of embodiments 1 to 6, 8 to 10 except as dependent on embodiment 7, 11 to 13, and 15 to 16 except as dependent on claim 14, wherein the peptide therapeutic agent is a parathyroid hormone-related protein.

19. The medical device of embodiment 18, wherein the peptide therapeutic agent is a parathyroid hormone -related protein (PTHrP) analogue represented by formula

[Glu22'25,Leu23'28'31,Aib29,Lys26'30]hPTHrP(l-34)NH2.

20. The medical device of any preceding embodiment, wherein the coating is present on the microneedles in an average amount of 0.01 to 2 micrograms per microneedle. 21. A method of making a medical device comprising microneedles, the method comprising:

providing an aqueous composition comprising a peptide therapeutic agent, an amino acid, and a buffer, wherein the peptide therapeutic agent and the amino acid either both have a net positive charge or both have a net negative charge in the aqueous composition;

contacting the microneedles with the aqueous composition; and

volatilizing a portion of the aqueous composition to provide a coating on at least a portion of the microneedles, wherein the coating comprises at least the peptide therapeutic agent and the amino acid.

22. The method of embodiment 21, wherein the buffer comprises phosphate, acetate, citrate, or tris(hydroxymethyl)aminomethane.

23. A method of stabilizing a peptide therapeutic agent in a coating on an array of microneedles, the method comprising incorporating an amino acid into the coating, wherein the peptide therapeutic agent and the amino acid either both have a net positive charge or both have a net negative charge.

24. The method of any one of embodiments 21 to 23, wherein the molar ratio of the amino acid to the peptide therapeutic agent is less than 2: 1.

25. The method of any one of embodiments 21 to 23, wherein the molar ratio of the amino acid to the peptide therapeutic agent is in a range from 0.5: 1 to 55 : 1.

26. The method of any one of embodiments 21 to 25, wherein the amino acid is histidine, arginine, lysine, aspartic acid, or glutamic acid. 27. The method of embodiment 26, wherein the amino acid is histidine.

28. The method of any one of embodiments 21 to 27, wherein the amino acid is present in the coating in a range from 0.1 to 15 percent by weight, based on the total weight of the coating. 29. The method of any one of embodiments 21 to 28, wherein the aqueous composition has a pH in a range from 3 to 11.

30. The method of any one of embodiments 21 to 29, wherein the aqueous composition or the coating is substantially free of sorbitol.

31. The method of any one of embodiments 21 to 30, wherein the peptide therapeutic agent and the amino acid each have a net positive charge. 32. The method of any one of embodiments 21 to 30, wherein the peptide therapeutic agent and the amino acid each have a net negative charge. 33. A method of making a medical device comprising microneedles, the method comprising:

providing an aqueous composition comprising a peptide therapeutic agent, histidine, and a buffer, wherein the molar ratio of the histidine to the peptide therapeutic agent in the aqueous composition is less than 2: 1 ;

contacting the microneedles with the aqueous composition; and

volatilizing a portion of the aqueous composition to provide a coating on at least a portion of the microneedles, wherein the coating comprises at least the peptide therapeutic agent and the histidine.

34. The method of embodiment 33, wherein the aqueous composition has a pH in a range from 3 to 11.

35. The method of embodiment 33 or 34, wherein the molar ratio of histidine to the peptide therapeutic agent is less than 1.5: 1.

36. The method of any one of embodiments 33 to 35, wherein histidine is present in the coating in a range from 0.1 to 15 percent by weight, based on the total weight of the coating.

37. The method of any one of embodiments 33 to 36, wherein buffer comprises phosphate, acetate, citrate, or tris(hydroxymethyl)aminomethane. 38. The method of any one of embodiments 33 to 37, wherein the peptide therapeutic agent has a net positive charge.

39. The method of any one of embodiments 33 to 37, wherein the peptide therapeutic agent has a net negative charge.

40. The method of any one of embodiments 21 to 39, wherein the wherein the peptide therapeutic agent is parathryroid hormone, calcitonin, lysozyme, insulin, glatiramer acetate, goserelin acetate, octreotide, leuprolide, vasopressin, atrial natriuretic peptide(ANP), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), erythropoietin(EPO), bone morphogenetic proteins(BMPs), epidermal growth factor(EFG), granulocyte clony-stimulating factor (G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF), interferon alpha, interferon beta, interferon gamma, antimicrobial peptides, dornase alfa, tissue plasminogen activator, a fusion protein, or a vaccine. 41. The method of any one of embodiments 21 to 40, wherein the coating is present on the microneedles in an average amount of 0.01 to 2 micrograms per microneedle. 42. A method of making a medical device comprising microneedles according to any one of embodiments 1 to 10, the method comprising:

providing an aqueous composition comprising the peptide therapeutic agent and the amino acid; contacting the microneedles with the aqueous composition; and

volatilizing a portion of the aqueous composition to provide a coating on at least a portion of the microneedles, wherein the coating comprises at least the peptide therapeutic agent and the amino acid.

43. A method of making a medical device comprising microneedles according to any one of embodiments 11 to 16, the method comprising:

providing an aqueous composition comprising the peptide therapeutic agent and the histidine; contacting the microneedles with the aqueous composition; and

volatilizing a portion of the aqueous composition to provide a coating on at least a portion of the microneedles, wherein the coating comprises at least the peptide therapeutic agent and the histidine.

44. The method of any one of embodiments 21 to 31, 33 to 38, 42, and 43, wherein the peptide therapeutic agent is a parathyroid hormone -related protein.

45. The method of embodiment 44, wherein the peptide therapeutic agent is a parathyroid hormone- related protein (PTHrP) analogue represented by formula

[Glu22'25,Leu23'28'31,Aib29,Lys26'30]hPTHrP(l-34)NH2.

The following examples are provided to more particularly illustrate various embodiments of the present invention, but the particular materials and amounts thereof recited in these examples, as well as other conditions and details are in no way intended to limit this invention.

EXAMPLES

Materials

The microneedle arrays were injection molded using VECTRA MT 1300 thermoplastic liquid crystal polymer (LCP) (Ticona Engineering Polymers, Florence, KY). The microneedle arrays featured four-sided pyramidal shaped microneedles having heights of about 500 microns and an aspect ratio of approximately 3: 1. The microneedles were arranged in an octagon shaped pattern of about 316 microneedles with equal spacing between individual microneedles of about 550 microns (as measured from tip to tip).

PTH, parathyroid hormone (1-34) (human), was obtained as the acetate salt from Bachem, Torrence, CA. Salmon calcitonin and lysozme were obtained from Calbiochem, LaJolla, CA. Insulin was obtained from Sigma-Aldrich, St. Louis, MO. The parathyroid hormone -related protein (PTHrP) analogue [Glu22'25,Leu23'28'31,Aib29,Lys26'30]hPTHrP(l-34)NH2 was obtained as a lyophilized powder having a combined acetate and water content of approximately 15 weight percent (supplied by Lonza Braine SA, Braine, Belgium).

L-Histidine monohydrochloride (His-HCl) was obtained from J.T. Baker, Phillipsburg, NJ.

L-Arginine hydrochloride (Arg-HCl) was obtained from Spectrum Chemical, New Brunswick,

NJ.

Phosphate buffered saline (IX PBS) was obtained from Amresco LLC, Solon, OH.

The protein or polypeptide content in the formulation coated on the microneedle arrays was determined using an Agilent 1100 HPLC system (Agilent Technologies, Wilmington, DE) equipped with a binary pump, well-plated thermostated autosampler, thermostated column compartment, and a diode array UV detector. A Zorbax 300SB-C8 column (Agilent Technologies, Wilmington, DE) having a 5 μιη particle size and 2.1x150 mm inner diameter was used for the separations. The column was maintained at 50 °C. The mobile phase consisted of two eluents. Eluent A was 0.1% TFA (trifluoroacetic acid) in water and eluent B was 0.1% TFA in acetonitrile (Spectrum Chemical, New Brunswick, NJ). A linear gradient from 80/20 to 50/50 (A/B) was applied over 30 minutes. The flow rate was 0.4 mL/minute and the UV detection wavelength was set at 214 nm. The total run time was 34 minutes and the sample injection volume was 15 μί.

The pH of the formulations was determined using pH color indicating strips (available from EMD Chemicals, Gibbstown, NJ under the trade designation "COLORpHAST").

Example 1

A sample formulation containing 10 mg/mL of PTH and 12 mg/mL of L-histidine

monohydrochloride (His-HCl) in phosphate buffered saline (PBS) was prepared. The pH of the sample formulation was 5.5-6.0. A control formulation was also prepared containing 10 mg/mL of PTH in PBS. The control formulation did not have His-HCl in the formulation. The pH of the control formulation was 6.0. Microneedle arrays were coated with either the sample or the control formulation. The coating was applied by dropwise addition of 50 of the formulation to the portion of the array defined by the octagon shaped pattern of microneedles. The flood coated arrays (both sample and control formulation coated) were dried in an oven at 35 °C for about 15 hours.

After drying, the coated arrays were placed in a storage chamber that was maintained at 40 °C and

96 % relative humidity (RH). The PTH content of the coated arrays was determined following storage in the chamber for 1, 3, 7, and 14 days. At the designated time point, an array was taken from the chamber and washed with PBS (2mL) to remove the coating from the array. An aliquot of the resulting wash solution was analyzed for PTH content using the HPLC method described above. Reference standards were prepared by measuring the initial PTH content of freshly coated arrays (both sample and control formulation coated). The arrays used as reference standards were stored in a refrigerator at about 4 °C and analyzed within one day of being prepared. At each time point, the percentage of undegraded PTH remaining in the sample or control coatings was determined by measuring the peak area for PTH in the selected coating and dividing it by the peak area measured for PTH in the corresponding reference standard. The results are reported in Table 1.

Table 1.

Figure imgf000025_0001

Example 2

The same procedure as described in Example 1 was used with the exception that the sample formulation contained 12 mg/mL of L-arginine hydrochloride, instead of L-histidine monohydrochloride. The pH of the sample formulation was 6.0. The results are reported in Table 2.

Table 2.

Figure imgf000025_0002

Example 3

A sample formulation containing 5 mg/mL of salmon calcitonin and 12 mg/mL of L-histidine monohydrochloride (His-HCl) in PBS was prepared. The pH of the sample formulation was 5.5. A control formulation was also prepared containing 5 mg/mL of salmon calcitonin in PBS. The control formulation did not have His-HCl in the formulation. The pH of the control formulation was 6.0-6.5. Microneedle arrays were coated with either the sample or the control formulation. The coating was applied by dropwise addition of 50 of the formulation to the portion of the array defined by the octagon shaped pattern of microneedles. The flood coated arrays (both sample and control formulation coated) were dried in an oven at 35 °C for about 15 hours.

After drying, the coated arrays were placed in a storage chamber that was maintained at 40 °C and 96 % relative humidity (RH). The salmon calcitonin content of the coated arrays was determined following storage in the chamber for 1, 3, 7, and 14 days. At the designated time point, an array was taken from the chamber and washed with PBS (ImL) to remove the coating from the array. An aliquot of the resulting wash solution was analyzed for salmon calcitonin content using the HPLC method described above. Reference standards were prepared by measuring the initial salmon calcitonin content of freshly coated arrays (both sample and control formulation coated). The arrays used as reference standards were stored in a refrigerator at about 4 °C and analyzed within one day of being prepared. The percentage of undegraded salmon calcitonin remaining in the coating at each time point was determined by measuring the peak area for salmon calcitonin in the selected coating and dividing it by the peak area measured for salmon calcitonin in the corresponding reference standard. The results are reported in Table 3.

Table 3.

Figure imgf000026_0001

Example 4

The same procedure as described in Example 3 was used with the exception that the sample formulation contained 12 mg/mL of L-arginine hydrochloride, instead of L-histidine monohydrochloride. The pH of the sample formulation was 6.0-6.5. The results are reported in Table 4.

Table 4.

Figure imgf000026_0002

Example 5

A sample formulation containing 5 mg/mL of insulin and 12 mg/mL of L-histidine

monohydrochloride (His-HCl) in 0.1 N acetic acid was prepared. The pH of the sample formulation was 3.0-3.5. A control formulation was also prepared containing 5 mg/mL of insulin in 0.1 N acetic acid. The control formulation did not have His-HCl in the formulation. The pH of the control formulation was 3.0- 3.5. Microneedle arrays were coated with either the sample or the control formulation. The coating was applied by dropwise addition of 50 of the formulation to the portion of the array defined by the octagon shaped pattern of microneedles. The flood coated arrays (both sample and control formulation coated) were dried in an oven at 35 °C for about 15 hours.

After drying, the coated arrays were placed in a storage chamber that was maintained at 40 °C and 96 % relative humidity (RH). The insulin content of the coated arrays was determined following storage in the chamber for 1, 3, 7, and 14 days. At the designated time point, an array was taken from the chamber and washed with 0.1 N acetic acid (1 mL) to remove the coating from the array. The resulting wash solution was analyzed for insulin content using the HPLC method described above. Reference standards were prepared by measuring the insulin content of freshly coated arrays (both sample and control formulation coated). The arrays used as reference standards were stored in a refrigerator at about 4 °C and analyzed within one day of being prepared. The percentage of undegraded insulin remaining in the coating at each time point was determined by measuring the peak area for insulin in the selected coating and dividing it by the peak area measured for insulin in the corresponding reference standard. The results are reported in Table 5.

Table 5.

Figure imgf000027_0001

Example 6

The same procedure as described in Example 5 was used with the exception that the sample formulation contained 12 mg/mL of L-arginine hydrochloride, instead of L-histidine monohydrochloride. The pH of the sample formulation was 3.0-3.5. The results are reported in Table 6.

Table 6.

Figure imgf000027_0002
Example 7

A sample formulation containing 10 mg/mL of lysozyme and 12 mg/mL of L-histidine monohydrochloride (His-HCl) in PBS was prepared. The pH of the sample formulation was 5.5-6.0. A control formulation was also prepared containing 10 mg/mL of lysozyme in PBS. The control formulation did not have His-HCl in the formulation. The pH of the control formulation was 6.5.

Microneedle arrays were coated with either the sample or the control formulation. The coating was applied by dropwise addition of 50 of the formulation to the portion of the array defined by the octagon shaped pattern of microneedles. The flood coated arrays (both sample and control formulation coated) were dried in an oven at 35 °C for about 15 hours.

After drying, the coated arrays were placed in a storage chamber that was maintained at 40 °C and 96 % relative humidity (RH). The lysozyme content of the coated arrays was determined following storage in the chamber for 1, 3, 7, and 14 days. At the designated time point, an array was taken from the chamber and washed with PBS (2 mL) to remove the coating from the array. An aliquot of the resulting wash solution was analyzed for lysozyme content using the HPLC method described above. Reference standards were prepared by measuring the lysozyme content of freshly coated arrays (both sample and control formulation coated). The arrays used as reference standards were stored in a refrigerator at about 4 °C and analyzed within one day of being prepared. The percentage of undegraded lysozyme remaining in the coating at each time point was determined by measuring the peak area for lysozyme in the selected coating and dividing it by the peak area measured for lysozyme in the corresponding reference standard. The results are reported in Table 7.

Table 7.

Figure imgf000028_0002

Example 8

The same procedure as described in Example 7 was used with the exception that the sample formulation contained 12 mg/mL of L-arginine hydrochloride, instead of L-histidine monohydrochloride. The pH of the sample formulation was 6.5. The results are reported in Table 8.

Table 8.

Figure imgf000028_0003

Example 9

A sample formulation containing 20 mg/mL of [Glu22'25,Leu23'28'31,Aib29,Lys26'30]hPTHrP(l- 34)NH2 and 20 mg/mL of L-histidine monohydrochloride (His-HCl) in PBS was prepared. A control formulation was also prepared containing 20 mg/mL of [Glu22'25,Leu23'28'31,Aib29,Lys26'30]hPTHrP(l- 34)NH2 in PBS. The control formulation did not have His-HCl in the formulation. Microneedle arrays were coated with either the sample or the control formulation. The coating was applied by dropwise addition of 50 of the formulation to the portion of the array defined by the octagon shaped pattern of microneedles. The flood coated arrays (both sample and control formulation coated) were dried in an oven at 35 °C for 2 hours followed by 30 °C for 15 hours.

After drying, the coated arrays were placed in a storage chamber that was maintained at 40 °C and 96 % relative humidity (RH). The [Glu22'25,Leu23'28'31,Aib29,Lys26'30]hPTHrP(l-34)NH2 content of the coated arrays was determined following storage in the chamber for 1, 3, and 7 days. The initial

[Glu22'25,Leu23'28'31,Aib29,Lys26'30]hPTHrP(l-34)NH2 content was also determined using freshly coated arrays (both sample and control formulation coated). The arrays used to determine initial content were stored in a refrigerator at about 4 °C and analyzed within one day of being prepared. At the designated time point, an array was taken from the chamber and washed with 0.1 N acetic acid (20 mL) to remove the formulation from the array. The resulting wash solution was analyzed for

[Glu22'25,Leu23'28'31,Aib29,Lys26'30]hPTHrP(l-34)NH2 content using the HPLC method described above.

The results were quantified against an external standard of

Figure imgf000028_0001

34)NH2. At each time point, the percent purity of [Glu22'25,Leu23'28'31,Aib29,Lys26'30]hPTHrP(l-34)NH2 in the coating was determined by measuring the peak area for

Figure imgf000029_0001

34)NH2 in the selected coating and dividing it by the total peak area measured for all

[Glu22'25,Leu23'28'31,Aib29,Lys26'30]hPTHrP(l-34)NH2 related peaks. The results are reported in Table 9. Table 9.

Figure imgf000029_0002

Example 10

The same procedure as described in Example 9 was used with the exception that the sample formulation contained 20 mg/mL of L-arginine hydrochloride, instead of L-histidine monohydrochloride. The results are reported in Table 10.

Table 10.

Figure imgf000029_0003

Example 11

A sample formulation containing 10 mg/mL of [Glu22'25,Leu23'28'31,Aib29,Lys26'30]hPTHrP(l-

34)NH2 and 10 mg/mL of L-histidine monohydrochloride (His-HCl) in PBS was prepared. A control formulation was also prepared containing 10 mg/mL of [Glu 22 ' 25 ,Leu 23 ' 28 ' 31 ,Aib 29 ,Lys 26 ' 30 ]hPTHrP(l- 34)NH2 in PBS. The control formulation did not have His-HCl in the formulation. Microneedle arrays were coated with either the sample or the control formulation. The coating was applied by dropwise addition of 40 of the formulation to the portion of the array defined by the octagon shaped pattern of microneedles. The coated arrays (both sample and control formulation coated) were dried in an oven at 35 °C for 1.5 hours followed by 30 °C for 15 hours.

After drying, the coated arrays were placed in a storage chamber that was maintained at either 25 °C/ 60 % RH or 5 °C/ ambient RH. The [Glu22'25,Leu23'28'31,Aib29,Lys26'30]hPTHrP(l-34)NH2 content of the coated arrays was determined following storage in the chamber for 7 days, 14 days, 28 days, and 2 months. The initial [Glu22'25,Leu23'28'31,Aib29,Lys26'30]hPTHrP(l-34)NH2 content was also determined using freshly coated arrays (both sample and control formulation coated). The arrays used to determine initial content were stored in a refrigerator at about 4 °C and analyzed within one day of being prepared. At the designated time point, an array was taken from the chamber and washed with PBS (3.5 mL) to remove the coating from the array. An aliquot of the resulting wash solution was analyzed for [Glu22'25,Leu23'28'31,Aib29,Lys26'30]hPTHrP(l-34)NH2 content using the HPLC method described above.

The results were quantified against an external standard of

Figure imgf000030_0001

34)NH2. At each time point, the percent purity of [Glu22'25,Leu23'28'31,Aib29,Lys26'30]hPTHrP(l-34)NH2 in the coating was determined by measuring the peak area for

Figure imgf000030_0002

34)NH2 in the selected coating and dividing it by the total peak area measured for all

[Glu22'25,Leu23'28'31,Aib29,Lys26'30]hPTHrP(l-34)NH2 related peaks. The results are reported in Table 11.

Table 11.

Figure imgf000030_0003

Example 12

The same procedure as described in Example 10 was used with the exception that the sample formulation contained 10 mg/mL of L-arginine hydrochloride, instead of L-histidine monohydrochloride. The results are reported in Table 12.

Table 12.

Figure imgf000030_0004

Example 13

Five sample formulations were prepared containing 10 mg/mL of

[Glu22'25,Leu23'28'31,Aib29,Lys26'30]hPTHrP(l-34)NH2 and varying concentrations of L-histidine monohydrochloride (His-HCl) in PBS. The concentrations of His-HCl in the sample formulations range from 1 mg/mL to 10 mg/mL. A control formulation was also prepared containing 10 mg/mL of

[Glu22'25,Leu23'28'31,Aib29,Lys26'30]hPTHrP(l-34)NH2 in PBS. The control formulation did not have His- HCl in the formulation. Microneedle arrays were coated with either the sample or the control formulations. The coating was applied by dropwise addition of 40 of the formulation to the portion of the array defined by the octagon shaped pattern of microneedles. The flood coated arrays (both sample and control formulation coated) were dried in an oven at 35 °C for 1.5 hours followed by 30 °C for 15 hours. After drying, the coated arrays were placed in a storage chamber that was maintained at one of three storage conditions: 40 °CI 96% RH (storage condition A); 25 °CI 60% RH (storage condition B); or 5 °C/ ambient RH. The [Glu22'25,Leu23'28'31,Aib29,Lys26'30]hPTHrP(l-34)NH2 content of the coated arrays was determined following storage in a chamber for lday, 3 days,7 days, 14 days, 21 days, 28 days, and 2 months. The initial [Glu22'25,Leu23'28'31,Aib29,Lys26'30]hPTHrP(l-34)NH2 content was also determined using freshly coated arrays (both sample and control formulation coated). The arrays used to determine initial content were stored in a refrigerator at about 4 °C and analyzed within one day of being prepared. At the designated time point, an array was taken from the chamber and washed with PBS (3.5 mL) to remove the coating from the array. An aliquot of the resulting wash solution was analyzed for

[Glu22'25,Leu23'28'31,Aib29,Lys26'30]hPTHrP(l-34)NH2 content using the HPLC method described above.

22 25 23 28 31 29 26 30

The results were quantified against an external standard of [Glui iJ,LeuiJ i°'J1,Aib^,LysiU JU]hPTHrP(l- 34)NH2. At each time point, the percent purity of [Glu22'25,Leu23'28'31,Aib29,Lys26'30]hPTHrP(l-34)NH2 in

22 25 23 28 31 29 26 30

the coating was determined by measuring the peak area for [Glui iJ,LeuiJ i°'J1,Aib^,Lysi"'JU]hPTHrP(l- 34)NH2 in the selected coating and dividing it by the total peak area measured for all

[Glu22'25,Leu23'28'31,Aib29,Lys26'30]hPTHrP(l-34)NH2 related peaks. The results are reported in Table 13.

Table 13.

Figure imgf000031_0001

(a) the sample for analysis contained insoluble impurities. ND = not determined

Example 14

Three formulations were prepared using [Glu22'25,Leu23'28'31,Aib29,Lys26'30]hPTHrP(l-34)NH2 as the polypeptide component. Formulation 1 contained [Glu22'25,Leu23'28'31,Aib29,Lys26'30]hPTHrP(l-34)NH2 (51 weight percent) in PBS. Formulation 2 contained [Glu22'25,Leu23'28'31,Aib29,Lys26'30]hPTHrP(l-34)NH2 (51 weight percent) and L-histidine monohydrochloride (3 weight percent) in PBS. Formulation 3 contained [Glu22'25,Leu23'28'31,Aib29,Lys26'30]hPTHrP(l-34)NH2 (49 weight percent) and L-histidine monohydrochloride (5 weight percent) in PBS. The pH of Formulation 1 was 5.5. The pH of both Formulation 2 and Formulation 3 was 5.0. The formulations were coated on microneedle arrays using the dip-coating procedure described in FIGS. lOA-C and Example 16 of United States Patent Application Publication No. 2008/0051699 (Choi, et al.)). The coated arrays were then dried in an oven at 35 °C for 2 hours.

After drying, the coated arrays were placed into a packaging system consisting of a polycarbonate collar in a polyester pod sealed with Tyvek film. Each packaged array was then sealed in a 7x10 foil pouch (Oliver-Tolas Healthcare Packaging, Feasterville, PA). The sealed pouches were placed in a storage chamber that was maintained at one of three storage conditions: 40 °C/ 75% RH (storage condition D); 25 °CI 60% RH (storage condition B); or 5 °CI ambient RH (storage condition C). The [Glu22'25,Leu23'28'31,Aib29,Lys26'30]hPTHrP(l-34)NH2 content of the coated arrays was determined following storage in a chamber for 2 weeks, 1 month, and 2 months, and 3 months. The initial

[Glu22'25,Leu23'28'31,Aib29,Lys26'30]hPTHrP(l-34)NH2 content was also determined using freshly coated arrays that were not placed in a storage chamber. The arrays used to determine initial content were stored in a refrigerator at about 4 °C and analyzed within one day of being prepared. At the designated time point, an array was taken from the chamber and washed with 0.1 N acetic acid (1-3 mL) to remove the coating from the array. An aliquot of the resulting wash solution was analyzed for

[Glu22'25,Leu23'28'31,Aib29,Lys26'30]hPTHrP(l-34)NH2 content using the HPLC method described above.

22 25 23 28 31 29 26 30

The results were quantified against an external standard of [Glui iJ,LeuiJ i°'J1,Aib^,LysiU JU]hPTHrP(l- 34)NH2. At each time point, the percent purity of [Glu22'25,Leu23'28'31,Aib29,Lys26'30]hPTHrP(l-34)NH2 in the coating was determined by measuring the peak area for

Figure imgf000032_0001

34)NH2 in the selected coating and dividing it by the total peak area measured for all

[Glu22'25,Leu23'28'31,Aib29,Lys26'30]hPTHrP(l-34)NH2 related peaks. The results are reported in Table 14 as the mean value obtained for 5 replicates.

Table 14.

Figure imgf000033_0001

ND = not determined This disclosure may take on various modifications and alterations without departing from its spirit and scope. Accordingly, this disclosure is not limited to the above-described embodiments but is to be controlled by the limitations set forth in the following claims and any equivalents thereof.

Claims

WHAT IS CLAIMED IS:
1. A medical device comprising:
an array of microneedles; and
a coating on or within at least a portion of the microneedles, wherein the coating comprises: a peptide therapeutic agent; and
histidine,
wherein the molar ratio of the histidine to the peptide therapeutic agent is less than 2: 1.
2. The medical device of claim 1, wherein the molar ratio of the histidine to the peptide therapeutic agent is less than 1.5: 1.
3. The medical device of claim 1, wherein the peptide therapeutic agent has a net positive charge.
4. The medical device of claim 1, wherein the histidine stabilizes the peptide therapeutic agent in the coating.
5. A medical device comprising:
an array of microneedles; and
a coating on or within at least a portion of the microneedles, wherein the coating comprises: a peptide therapeutic agent; and
an amino acid,
wherein the peptide therapeutic agent and the amino acid either both have a net positive charge or both have a net negative charge, and wherein the coating is substantially free of sorbitol.
6. The medical device of claim 5, wherein the amino acid has a net positive charge.
7. The medical device of claim 6, wherein the amino acid is histidine.
8. The medical device of any one of claims 1 to 7, wherein the peptide therapeutic agent is a parathyroid hormone -related protein.
9. The medical device of claim 8, wherein the peptide therapeutic agent is a parathyroid hormone- related protein (PTHrP) analogue represented by formula
[Glu22'25,Leu23'28'31,Aib29,Lys26'30]hPTHrP(l-34)NH2.
10. A method of making a medical device comprising microneedles, the method comprising: providing an aqueous composition comprising a peptide therapeutic agent, an amino acid, and a buffer, wherein the peptide therapeutic agent and the amino acid either both have a net positive charge or both have a net negative charge in the aqueous composition;
contacting the microneedles with the aqueous composition; and
volatilizing a portion of the aqueous composition to provide a coating on at least a portion of the microneedles, wherein the coating comprises at least the peptide therapeutic agent and the amino acid.
11. The method of claim 10, wherein the aqueous composition has a pH in a range from 3 to 11.
12. A method of stabilizing a peptide therapeutic agent on or within an array of microneedles, the method comprising incorporating an amino acid into the array of microneedles, wherein the peptide therapeutic agent and the amino acid either both have a net positive charge or both have a net negative charge.
13. A method of making a medical device comprising microneedles, the method comprising:
providing an aqueous composition comprising a peptide therapeutic agent, histidine, and a buffer, wherein the molar ratio of the histidine to the peptide therapeutic agent in the aqueous composition is less than 2: 1 ;
contacting the microneedles with the aqueous composition; and
volatilizing a portion of the aqueous composition to provide a coating on at least a portion of the microneedles, wherein the coating comprises at least the peptide therapeutic agent and the histidine.
14. The method of any one of claims 10 to 13, wherein the peptide therapeutic agent is a parathyroid hormone -related protein.
15. The method of claim 14, wherein the peptide therapeutic agent is a parathyroid hormone -related protein (PTHrP) analogue represented by formula [Glu22'25,Leu23'28'31,Aib29,Lys26'30]hPTHrP(l-34)NH2.
PCT/US2012/067292 2011-11-30 2012-11-30 Microneedle device including a peptide therapeutic agent and an amino acid and methods of making and using the same WO2013082427A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US201161565247 true 2011-11-30 2011-11-30
US201161565227 true 2011-11-30 2011-11-30
US61/565,247 2011-11-30
US61/565,227 2011-11-30

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US14361787 US9623087B2 (en) 2011-11-30 2012-11-30 Microneedle device including a peptide therapeutic agent and an amino acid and methods of making and using the same
CA 2857502 CA2857502A1 (en) 2011-11-30 2012-11-30 Microneedle device including a peptide therapeutic agent and an amino acid and methods of making and using the same
BR112014013099A BR112014013099A2 (en) 2011-11-30 2012-11-30 microneedle device including a peptide therapeutic agent and an amino acid and methods for producing and using the device
EP20120852532 EP2785406A4 (en) 2011-11-30 2012-11-30 Microneedle device including a peptide therapeutic agent and an amino acid and methods of making and using the same
AU2012345777A AU2012345777B2 (en) 2011-11-30 2012-11-30 Microneedle device including a peptide therapeutic agent and an amino acid and methods of making and using the same
CN 201280059136 CN104080506B (en) 2011-11-30 2012-11-30 The microneedle device includes a therapeutic agent and a peptide amino acids and methods of making and use thereof
KR20147017389A KR20140097454A (en) 2011-11-30 2012-11-30 Microneedle device including a peptide therapeutic agent and an amino acid and methods of making and using the same
US15480813 US20170209367A1 (en) 2011-11-30 2017-04-06 Microneedle device having a peptide therapeutic agent and an amino acid and methods of making and using the same

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US201414361787 A-371-Of-International 2014-05-30 2014-05-30
US15480813 Continuation US20170209367A1 (en) 2011-11-30 2017-04-06 Microneedle device having a peptide therapeutic agent and an amino acid and methods of making and using the same

Publications (1)

Publication Number Publication Date
WO2013082427A1 true true WO2013082427A1 (en) 2013-06-06

Family

ID=47352020

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/US2012/067292 WO2013082427A1 (en) 2011-11-30 2012-11-30 Microneedle device including a peptide therapeutic agent and an amino acid and methods of making and using the same
PCT/US2012/067278 WO2013082418A1 (en) 2011-11-30 2012-11-30 Microneedle device having a peptide therapeutic agent and an amino acid, methods of making and using the same

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/US2012/067278 WO2013082418A1 (en) 2011-11-30 2012-11-30 Microneedle device having a peptide therapeutic agent and an amino acid, methods of making and using the same

Country Status (6)

Country Link
US (3) US9675675B2 (en)
EP (2) EP2785327A1 (en)
KR (2) KR20140097454A (en)
CN (2) CN104080506B (en)
CA (2) CA2857501A1 (en)
WO (2) WO2013082427A1 (en)

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8822663B2 (en) 2010-08-06 2014-09-02 Moderna Therapeutics, Inc. Engineered nucleic acids and methods of use thereof
US8980864B2 (en) 2013-03-15 2015-03-17 Moderna Therapeutics, Inc. Compositions and methods of altering cholesterol levels
US8999380B2 (en) 2012-04-02 2015-04-07 Moderna Therapeutics, Inc. Modified polynucleotides for the production of biologics and proteins associated with human disease
US9107886B2 (en) 2012-04-02 2015-08-18 Moderna Therapeutics, Inc. Modified polynucleotides encoding basic helix-loop-helix family member E41
WO2015129807A1 (en) * 2014-02-27 2015-09-03 久光製薬株式会社 Microneedle
US9186372B2 (en) 2011-12-16 2015-11-17 Moderna Therapeutics, Inc. Split dose administration
US9283287B2 (en) 2012-04-02 2016-03-15 Moderna Therapeutics, Inc. Modified polynucleotides for the production of nuclear proteins
US9303079B2 (en) 2012-03-30 2016-04-05 Moderna Therapeutics, Inc. Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins
US9334328B2 (en) 2010-10-01 2016-05-10 Moderna Therapeutics, Inc. Modified nucleosides, nucleotides, and nucleic acids, and uses thereof
US9428535B2 (en) 2011-10-03 2016-08-30 Moderna Therapeutics, Inc. Modified nucleosides, nucleotides, and nucleic acids, and uses thereof
US9464124B2 (en) 2011-09-12 2016-10-11 Moderna Therapeutics, Inc. Engineered nucleic acids and methods of use thereof
US9533047B2 (en) 2011-03-31 2017-01-03 Modernatx, Inc. Delivery and formulation of engineered nucleic acids
US9555014B2 (en) 2010-05-12 2017-01-31 Radius Health, Inc. Therapeutic regimens
US9572897B2 (en) 2012-04-02 2017-02-21 Modernatx, Inc. Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins
US9597380B2 (en) 2012-11-26 2017-03-21 Modernatx, Inc. Terminally modified RNA
KR101828591B1 (en) * 2014-05-22 2018-02-14 주식회사 주빅 Fabrication of Microstructures by CCDP Method
US9920044B2 (en) 2010-09-28 2018-03-20 Radius Pharmaceuticals, Inc. Selective androgen receptor modulators

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150359864A1 (en) * 2012-03-09 2015-12-17 Oncotherapy Science, Inc. Pharmaceutical composition containing peptides
US9775799B2 (en) * 2013-02-13 2017-10-03 Hisamitsu Pharmaceutical Co., Inc. Microneedle-coating composition and microneedle device
CA2923010A1 (en) * 2013-09-03 2015-03-12 Georgia Tech Research Corporation Thermally stable vaccine formulations and microneedles
WO2015190098A1 (en) * 2014-06-13 2015-12-17 凸版印刷株式会社 Needle-shaped body manufacturing method and needle-shaped body
WO2016036866A1 (en) * 2014-09-04 2016-03-10 Corium International, Inc. Microstructure array, methods of making, and methods of use
JPWO2016067956A1 (en) * 2014-10-27 2017-08-10 久光製薬株式会社 Microneedle devices containing genetically replaceable follicle stimulating hormone
CN107206066A (en) * 2015-01-27 2017-09-26 3M创新有限公司 Alum-containing coating formulations for microneedle vaccine patches
CN105126242A (en) * 2015-07-26 2015-12-09 北京化工大学 Polymer coating microneedle patch convenient for antibiotic skin testing and preparation method thereof
JP2017047075A (en) * 2015-09-04 2017-03-09 久光製薬株式会社 Method of manufacture of microneedle device
CN108697881A (en) * 2015-10-09 2018-10-23 雷迪厄斯健康公司 PTHrP analogs formulation, a transdermal patch and its use

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020107505A1 (en) * 1995-06-06 2002-08-08 Alza Corporation Modification of polypeptide drugs to increase electrotransport flux
WO2005113008A1 (en) * 2004-05-21 2005-12-01 Mediplex Corp. Delivery agents for enhancing mucosal absorption of therapeutic agents
KR20060126063A (en) * 2005-06-03 2006-12-07 재단법인 목암생명공학연구소 The stabilized parathyroid hormone composition comprising parathyroid hormone, buffer and stabilizing agent
US20070184096A1 (en) * 2005-12-28 2007-08-09 Alza Corporation Stable Therapeutic Formulations
US20080051699A1 (en) * 2004-11-18 2008-02-28 3M Innovative Properties Company Method Of Using A Film To Coat A Microneedle Array
KR20080110681A (en) * 2006-04-20 2008-12-18 암겐 인코포레이티드 Stable emulsion formulations
US20090069226A1 (en) * 2004-05-28 2009-03-12 Amylin Pharmaceuticals, Inc. Transmucosal delivery of peptides and proteins

Family Cites Families (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3939346A1 (en) 1989-11-29 1991-06-06 Behringwerke Ag Arzneimittel for subcutaneous or intramuskulaeren application-containing polypeptide
GB9930882D0 (en) 1999-12-30 2000-02-23 Nps Allelix Corp GLP-2 formulations
US7186683B2 (en) 2000-09-18 2007-03-06 Sanos Bioscience A/S Use of GLP for the treatment, prevention, diagnosis, and prognosis of bone-related and nutrition-related disorders
US6881203B2 (en) 2001-09-05 2005-04-19 3M Innovative Properties Company Microneedle arrays and methods of manufacturing the same
EP1539212A4 (en) 2002-07-12 2007-05-02 Medarex Inc Methods and compositions for preventing oxidative degradation of proteins
KR20060029162A (en) * 2003-06-30 2006-04-04 알자 코포레이션 Method for coating skin piercing microprojections
US7141544B2 (en) 2003-10-10 2006-11-28 Baxter International, Inc. Stabilization of pharmaceutical protein formulations with small peptides
CA2587780A1 (en) 2004-11-18 2006-05-26 Transpharma Medical Ltd. Combined micro-channel generation and iontophoresis for transdermal delivery of pharmaceutical agents
EP1838290A2 (en) * 2005-01-21 2007-10-03 Alza Corporation Therapeutic peptide formulations for coating microneedles with improved stability containing at least one counterion
CN101466393A (en) 2006-03-15 2009-06-24 阿尔扎公司 Method for transdermal delivery of parathyroid hormone agents to prevent or treat osteopenia
JP5375611B2 (en) 2006-10-03 2013-12-25 ラジウス ヘルス,インコーポレイテッド Drug delivery methods for protein with bone anabolism
US7803770B2 (en) 2006-10-03 2010-09-28 Radius Health, Inc. Method of treating osteoporosis comprising administration of PTHrP analog
CA2686093C (en) 2007-04-16 2018-05-08 Corium International, Inc. Solvent-cast microneedle arrays containing active
GB0707938D0 (en) 2007-04-25 2007-05-30 Univ Strathclyde Precipitation stabilising compositions
US8450481B2 (en) 2007-06-14 2013-05-28 The Regents Of The University Of California Compounds for inhibiting protein aggregation, and methods for making and using them
US20120150023A1 (en) 2007-08-06 2012-06-14 Kaspar Roger L Microneedle arrays for active agent delivery
US20090117158A1 (en) * 2007-10-23 2009-05-07 Mahmoud Ameri Transdermal sustained release drug delivery
EP2052736A1 (en) 2007-10-26 2009-04-29 Nycomed Danmark ApS Parathyroid hormone formulations und uses thereof
CN101795680A (en) 2007-11-16 2010-08-04 波苏蛋白试剂公司 excipients for protein stabilization
WO2010022176A1 (en) 2008-08-19 2010-02-25 Ferring International Center S.A. Methods of treatment for skeletal conditons
JP2012509106A (en) 2008-11-18 2012-04-19 スリーエム イノベイティブ プロパティズ カンパニー Hollow microneedle arrays and methods
KR101634836B1 (en) 2008-12-26 2016-06-29 히사미쓰 세이야꾸 가부시키가이샤 Microneedle device
US20100203014A1 (en) 2009-02-04 2010-08-12 Aegis Therapeutics Llc Zwitterionic buffered acidic peptide and protein formulations
DE102009001636A1 (en) 2009-03-18 2010-09-23 Henkel Ag & Co. Kgaa Bleach bleach with delayed start
WO2010124255A3 (en) 2009-04-24 2011-02-03 Corium International, Inc. Methods for manufacturing microprojection arrays
RU2508135C2 (en) 2009-07-31 2014-02-27 3М Инновейтив Пропертиз Компани Hollow microneedle matrix
CA2779577A1 (en) 2009-11-02 2011-05-05 Therapeomic Ag Stabilized protein formulations and use thereof
CN101912600B (en) 2010-01-11 2014-01-29 杨国汉 Method for improving stability of insulin in solution
US9687641B2 (en) 2010-05-04 2017-06-27 Corium International, Inc. Method and device for transdermal delivery of parathyroid hormone using a microprojection array
US20130006217A1 (en) * 2011-04-22 2013-01-03 Gary Hattersley METHOD OF DRUG DELIVERY FOR PTH, PTHrP AND RELATED PEPTIDES

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020107505A1 (en) * 1995-06-06 2002-08-08 Alza Corporation Modification of polypeptide drugs to increase electrotransport flux
WO2005113008A1 (en) * 2004-05-21 2005-12-01 Mediplex Corp. Delivery agents for enhancing mucosal absorption of therapeutic agents
US20090069226A1 (en) * 2004-05-28 2009-03-12 Amylin Pharmaceuticals, Inc. Transmucosal delivery of peptides and proteins
US20080051699A1 (en) * 2004-11-18 2008-02-28 3M Innovative Properties Company Method Of Using A Film To Coat A Microneedle Array
KR20060126063A (en) * 2005-06-03 2006-12-07 재단법인 목암생명공학연구소 The stabilized parathyroid hormone composition comprising parathyroid hormone, buffer and stabilizing agent
US20070184096A1 (en) * 2005-12-28 2007-08-09 Alza Corporation Stable Therapeutic Formulations
KR20080110681A (en) * 2006-04-20 2008-12-18 암겐 인코포레이티드 Stable emulsion formulations

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP2785406A4 *

Cited By (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9555014B2 (en) 2010-05-12 2017-01-31 Radius Health, Inc. Therapeutic regimens
US9181319B2 (en) 2010-08-06 2015-11-10 Moderna Therapeutics, Inc. Engineered nucleic acids and methods of use thereof
US9937233B2 (en) 2010-08-06 2018-04-10 Modernatx, Inc. Engineered nucleic acids and methods of use thereof
US8822663B2 (en) 2010-08-06 2014-09-02 Moderna Therapeutics, Inc. Engineered nucleic acids and methods of use thereof
US9447164B2 (en) 2010-08-06 2016-09-20 Moderna Therapeutics, Inc. Engineered nucleic acids and methods of use thereof
US9920044B2 (en) 2010-09-28 2018-03-20 Radius Pharmaceuticals, Inc. Selective androgen receptor modulators
US10064959B2 (en) 2010-10-01 2018-09-04 Modernatx, Inc. Modified nucleosides, nucleotides, and nucleic acids, and uses thereof
US9334328B2 (en) 2010-10-01 2016-05-10 Moderna Therapeutics, Inc. Modified nucleosides, nucleotides, and nucleic acids, and uses thereof
US9657295B2 (en) 2010-10-01 2017-05-23 Modernatx, Inc. Modified nucleosides, nucleotides, and nucleic acids, and uses thereof
US9950068B2 (en) 2011-03-31 2018-04-24 Modernatx, Inc. Delivery and formulation of engineered nucleic acids
US9533047B2 (en) 2011-03-31 2017-01-03 Modernatx, Inc. Delivery and formulation of engineered nucleic acids
US9464124B2 (en) 2011-09-12 2016-10-11 Moderna Therapeutics, Inc. Engineered nucleic acids and methods of use thereof
US10022425B2 (en) 2011-09-12 2018-07-17 Modernatx, Inc. Engineered nucleic acids and methods of use thereof
US9428535B2 (en) 2011-10-03 2016-08-30 Moderna Therapeutics, Inc. Modified nucleosides, nucleotides, and nucleic acids, and uses thereof
US9295689B2 (en) 2011-12-16 2016-03-29 Moderna Therapeutics, Inc. Formulation and delivery of PLGA microspheres
US9271996B2 (en) 2011-12-16 2016-03-01 Moderna Therapeutics, Inc. Formulation and delivery of PLGA microspheres
US9186372B2 (en) 2011-12-16 2015-11-17 Moderna Therapeutics, Inc. Split dose administration
US9303079B2 (en) 2012-03-30 2016-04-05 Moderna Therapeutics, Inc. Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins
US9221891B2 (en) 2012-04-02 2015-12-29 Moderna Therapeutics, Inc. In vivo production of proteins
US9255129B2 (en) 2012-04-02 2016-02-09 Moderna Therapeutics, Inc. Modified polynucleotides encoding SIAH E3 ubiquitin protein ligase 1
US9254311B2 (en) 2012-04-02 2016-02-09 Moderna Therapeutics, Inc. Modified polynucleotides for the production of proteins
US9220755B2 (en) 2012-04-02 2015-12-29 Moderna Therapeutics, Inc. Modified polynucleotides for the production of proteins associated with blood and lymphatic disorders
US9283287B2 (en) 2012-04-02 2016-03-15 Moderna Therapeutics, Inc. Modified polynucleotides for the production of nuclear proteins
US9216205B2 (en) 2012-04-02 2015-12-22 Moderna Therapeutics, Inc. Modified polynucleotides encoding granulysin
US9192651B2 (en) 2012-04-02 2015-11-24 Moderna Therapeutics, Inc. Modified polynucleotides for the production of secreted proteins
US9220792B2 (en) 2012-04-02 2015-12-29 Moderna Therapeutics, Inc. Modified polynucleotides encoding aquaporin-5
US9095552B2 (en) 2012-04-02 2015-08-04 Moderna Therapeutics, Inc. Modified polynucleotides encoding copper metabolism (MURR1) domain containing 1
US9149506B2 (en) 2012-04-02 2015-10-06 Moderna Therapeutics, Inc. Modified polynucleotides encoding septin-4
US8999380B2 (en) 2012-04-02 2015-04-07 Moderna Therapeutics, Inc. Modified polynucleotides for the production of biologics and proteins associated with human disease
US9114113B2 (en) 2012-04-02 2015-08-25 Moderna Therapeutics, Inc. Modified polynucleotides encoding citeD4
US9301993B2 (en) 2012-04-02 2016-04-05 Moderna Therapeutics, Inc. Modified polynucleotides encoding apoptosis inducing factor 1
US9107886B2 (en) 2012-04-02 2015-08-18 Moderna Therapeutics, Inc. Modified polynucleotides encoding basic helix-loop-helix family member E41
US9572897B2 (en) 2012-04-02 2017-02-21 Modernatx, Inc. Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins
US9827332B2 (en) 2012-04-02 2017-11-28 Modernatx, Inc. Modified polynucleotides for the production of proteins
US9050297B2 (en) 2012-04-02 2015-06-09 Moderna Therapeutics, Inc. Modified polynucleotides encoding aryl hydrocarbon receptor nuclear translocator
US9061059B2 (en) 2012-04-02 2015-06-23 Moderna Therapeutics, Inc. Modified polynucleotides for treating protein deficiency
US9878056B2 (en) 2012-04-02 2018-01-30 Modernatx, Inc. Modified polynucleotides for the production of cosmetic proteins and peptides
US9675668B2 (en) 2012-04-02 2017-06-13 Moderna Therapeutics, Inc. Modified polynucleotides encoding hepatitis A virus cellular receptor 2
US9782462B2 (en) 2012-04-02 2017-10-10 Modernatx, Inc. Modified polynucleotides for the production of proteins associated with human disease
US9814760B2 (en) 2012-04-02 2017-11-14 Modernatx, Inc. Modified polynucleotides for the production of biologics and proteins associated with human disease
US9828416B2 (en) 2012-04-02 2017-11-28 Modernatx, Inc. Modified polynucleotides for the production of secreted proteins
US9587003B2 (en) 2012-04-02 2017-03-07 Modernatx, Inc. Modified polynucleotides for the production of oncology-related proteins and peptides
US9089604B2 (en) 2012-04-02 2015-07-28 Moderna Therapeutics, Inc. Modified polynucleotides for treating galactosylceramidase protein deficiency
US9233141B2 (en) 2012-04-02 2016-01-12 Moderna Therapeutics, Inc. Modified polynucleotides for the production of proteins associated with blood and lymphatic disorders
US9597380B2 (en) 2012-11-26 2017-03-21 Modernatx, Inc. Terminally modified RNA
US8980864B2 (en) 2013-03-15 2015-03-17 Moderna Therapeutics, Inc. Compositions and methods of altering cholesterol levels
JPWO2015129807A1 (en) * 2014-02-27 2017-03-30 久光製薬株式会社 Microneedles
WO2015129807A1 (en) * 2014-02-27 2015-09-03 久光製薬株式会社 Microneedle
KR101828591B1 (en) * 2014-05-22 2018-02-14 주식회사 주빅 Fabrication of Microstructures by CCDP Method

Also Published As

Publication number Publication date Type
US20140343499A1 (en) 2014-11-20 application
KR20140096151A (en) 2014-08-04 application
KR20140097454A (en) 2014-08-06 application
CN104080506A (en) 2014-10-01 application
EP2785327A1 (en) 2014-10-08 application
US20170209367A1 (en) 2017-07-27 application
CA2857502A1 (en) 2013-06-06 application
EP2785406A4 (en) 2015-10-21 application
CN104080506B (en) 2017-03-08 grant
US9623087B2 (en) 2017-04-18 grant
CN104080441A (en) 2014-10-01 application
US9675675B2 (en) 2017-06-13 grant
CA2857501A1 (en) 2013-06-06 application
WO2013082418A1 (en) 2013-06-06 application
US20140330198A1 (en) 2014-11-06 application
EP2785406A1 (en) 2014-10-08 application

Similar Documents

Publication Publication Date Title
Daddona et al. Parathyroid hormone (1-34)-coated microneedle patch system: clinical pharmacokinetics and pharmacodynamics for treatment of osteoporosis
Pfützner et al. Technosphere™/Insulin—a new approach for effective delivery of human insulin via the pulmonary route
US20050089554A1 (en) Apparatus and method for enhancing transdermal drug delivery
US20050049549A1 (en) Method and device for enhancing transdermal agent flux
US20080269685A1 (en) Solvent-cast microneedle arrays containing active
US20040115167A1 (en) Drug delivery device and method having coated microprojections incorporating vasoconstrictors
US6855372B2 (en) Method and apparatus for coating skin piercing microprojections
US20070184096A1 (en) Stable Therapeutic Formulations
US20080051699A1 (en) Method Of Using A Film To Coat A Microneedle Array
US20090325860A1 (en) Compositions for intranasal delivery of human insulin and uses thereof
US7846488B2 (en) Masking method for coating a microneedle array
US20020177839A1 (en) Microprojection array having a beneficial agent containing coating
US20040265354A1 (en) Formulations for coated microprojections containing non-volatile counterions
US20050226922A1 (en) Apparatus and method for transdermal delivery of fentanyl-based agents
Rohloff et al. DUROS® Technology delivers peptides and proteins at consistent rate continuously for 3 to 12 months
US20060188555A1 (en) Therapeutic peptide formulations with improved stability
CN101687090A (en) Microneedle device and method for producing the same
US20050123507A1 (en) Formulations for coated microprojections having controlled solubility
US20080262416A1 (en) Microneedle Arrays and Methods of Preparing Same
US20050256045A1 (en) Apparatus and method for transdermal delivery of parathyroid hormone agents
US20090187160A1 (en) Methods and devices for delivering agents across biological barriers
US20060034903A1 (en) Apparatus and method for transdermal delivery of natriuretic peptides
US20110276028A1 (en) Method and device for transdermal delivery of parathyroid hormone using a microprojection array
US20100221314A1 (en) Microneedle Device
US20070299388A1 (en) Microprojection array application with multilayered microprojection member for high drug loading

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12852532

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase in:

Ref document number: 2857502

Country of ref document: CA

NENP Non-entry into the national phase in:

Ref country code: DE

REEP

Ref document number: 2012852532

Country of ref document: EP

ENP Entry into the national phase in:

Ref document number: 2012345777

Country of ref document: AU

Date of ref document: 20121130

Kind code of ref document: A

ENP Entry into the national phase in:

Ref document number: 20147017389

Country of ref document: KR

Kind code of ref document: A

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112014013099

Country of ref document: BR

ENP Entry into the national phase in:

Ref document number: 112014013099

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20140529